CN107001330A

CN107001330A - Histone demethylase inhibitors

Info

Publication number: CN107001330A
Application number: CN201580062304.3A
Authority: CN
Inventors: 扬·K·陈; 迈克尔·布伦南·华莱士
Original assignee: Quanticel Pharmaceuticals Inc
Current assignee: Celgene Quanticel Research Inc
Priority date: 2014-09-17
Filing date: 2015-09-14
Publication date: 2017-08-01
Also published as: CL2017000662A1; JP2017529347A; US9758517B2; EP3194387B1; CO2017003445A2; EP3194387A4; US20170326116A1; BR112017005510A2; WO2016044138A1; AU2015318111A1; US20160108032A1; IL251184A0; SG11201702119PA; JP6723663B2; KR20170048601A; US20180271843A1; JP2020169183A; MX2017003463A; ES2751464T3; US10016401B2

Abstract

The present invention generally relates to treating cancer and the composition and method of tumor disease.There is provided herein substituted Pyrrolopyridine derivatives compound and include the pharmaceutical composition of the compound.Motif compound and theme composition are useful for inhibition of histone demethylase.In addition, motif compound is useful for the treatment of cancer such as prostate cancer, breast cancer, carcinoma of urinary bladder, lung cancer and/or melanoma and similar cancer with theme composition.

Description

Histone demethylase inhibitors

Cross reference

This application claims the rights and interests for the U.S. Provisional Application 62/051,850 submitted for 17th in September in 2014, it is by drawing With being hereby incorporated by reference in its entirety.

Background

In the art, there is the demand for effective treating cancer and tumor disease.

Invention summary

There is provided herein substituted Pyrrolopyridine derivatives compound and include the pharmaceutical composition of the compound. Motif compound and theme composition are useful for inhibition of histone demethylase.In addition, motif compound and theme group Compound is to have for the treatment of cancer such as prostate cancer, breast cancer, carcinoma of urinary bladder, lung cancer and/or melanoma and similar cancer .Substituted Pyrrolopyridine derivatives compound described herein is based on the carboxylic acid at 7- or its biological electricity Sub- isostere and disubstituted pyrroles simultaneously [3,2-b] the pyridine member ring systems in second substituent of 2-.In various embodiments In, 2- bit substituents are selected from bicyclic heteroaryl group.

A kind of embodiment provides the compound of the structure with formula (I),

Or its pharmaceutically acceptable salt,

Wherein,

R¹It is hydrogen or alkyl；

R²It is hydrogen, halogen or alkyl；

G isOr

N is 0,1 or 2；

R³It is alkyl, carbocylic radical, carbocylic radical alkyl, heterocyclic radical or cycloheteroalkylalkyl；

R⁴It is halogen, alkyl, alkoxy, carbocylic radical, heterocyclic radical, aryl, heteroaryl or X-R⁵；

Wherein：

X is-(C₁-C₆) alkylidene-,-O- ,-S- or-NR¹-；And

R⁵It is carbocylic radical, heterocyclic radical, aryl or heteroaryl.

A kind of embodiment provides the compound comprising formula (I) or its pharmaceutically acceptable salt and at least one pharmacy The pharmaceutical composition of upper acceptable excipient.

A kind of embodiment provides the method for inhibition of histone demethylase, and methods described includes taking off histone Methylase is contacted with the compound of formula (I).

A kind of embodiment provides the method for being used for treating the cancer in its subject is needed, and methods described includes The compound comprising formula (I) or the composition of its pharmaceutically acceptable salt are applied to subject.

It is incorporated by reference into

All publications, patent and the patent application referred in this manual just as each single publication, specially Profit or patent application are instructed to specifically and individually be incorporated herein by reference in the identical degree that is incorporated by reference into.

Detailed description of the invention

As herein and used in appended claims, unless separately clearly dictated in context, otherwise odd number Form " one (a) ", " one (an) " and " being somebody's turn to do (the) " include plural referents.Thus, for example, " a kind of agent (an mentioned Agent a variety of such agent) " are included, and " cell (thecell) " mentioned is including mentioning to those skilled in the art Known one or more cells (or the multiple cells mentioned) and its equivalent, etc..When scope is used for physics herein Property such as molecular weight, or during chemical property such as chemical formula, it is intended that all combinations and sub-portfolio including scope and wherein Particular.Term " about " is when referring to numeral or during number range, it is intended that signified numeral or number range be The approximation of (or in statistics experimental error) in experimental variability (experimental variability), and therefore The numeral or number range can change between the numeral of statement or the 1% of number range and 15%.Term " including (comprising) " (and relevant term or " has such as " including (comprise) " or " including (comprises) " (having) " or " include (including) ") be not intended to exclude in some other embodiments such as any composition of matter Embodiment in, compositions described herein, method or technique, or the like " can be made up of the feature described " or " base It is made up of in sheet the feature described ".

Definition

As used in this description and in the appended claims, unless specified on the contrary, otherwise following term With the implication being indicated below.

" amino " refers to-NH₂Group.

" cyano group " refers to-CN groups.

" nitro " refers to-NO₂Group.

" oxa- " refers to-O- groups.

" oxo " refers to=O groups.

" thio " refers to=S groups.

" imino group " refers to=N-H groups.

" oximido " refers to=N-OH groups.

" diazanyl " refers to=N-NH₂Group.

" alkyl " refer to it is being individually made up of carbon atom and hydrogen atom, not comprising degree of unsaturation, with from one Straight chain or side chain hydrocarbon chain radical to 15 carbon atoms is (for example, C₁-C₁₅Alkyl).In certain embodiments, alkyl Comprising one to 13 carbon atom (for example, C₁-C₁₃Alkyl).In certain embodiments, alkyl includes one to eight carbon Atom is (for example, C₁-C₈Alkyl).In other embodiments, alkyl includes one to five carbon atom (for example, C₁-C₅Alkane Base).In other embodiments, alkyl includes one to four carbon atom (for example, C₁-C₄Alkyl).In other embodiments In, alkyl is comprising one to three carbon atom (for example, C₁-C₃Alkyl).In other embodiments, alkyl includes one to two Individual carbon atom is (for example, C₁-C₂Alkyl).In other embodiments, alkyl includes a carbon atom (for example, C₁Alkyl).At it In his embodiment, alkyl is comprising five to 15 carbon atoms (for example, C₅-C₁₅Alkyl).In other embodiments, alkyl Comprising five to eight carbon atoms (for example, C₅-C₈Alkyl).In other embodiments, alkyl includes two to five carbon atoms (for example, C₂-C₅Alkyl).In other embodiments, alkyl includes three to five carbon atoms (for example, C₃-C₅Alkyl). In other embodiments, alkyl group is selected from methyl, ethyl, 1- propyl group (n-propyl), 1- Methylethyls (isopropyl), 1- butyl (normal-butyl), 1- methyl-propyls (sec-butyl), 2- methyl-propyls (isobutyl group), 1,1- dimethyl ethyls (tert-butyl group), 1- amyl groups (n-pentyl).Alkyl is attached to the remainder of molecule by singly-bound.Unless specifically state in addition in this manual, it is no Then alkyl group is optionally replaced by the one or more in following substituent：Halogen, cyano group, nitro, oxo, thio, Asia Amino, oximido, trimethylsilyl ,-OR^a、-SR^a、-OC(O)-R^a、-N(R^a)₂、-C(O)R^a、-C(O)OR^a、-C(O)N (R^a)₂、-N(R^a)C(O)OR^a、-OC(O)-N(R^a)₂、-N(R^a)C(O)R^a、-N(R^a)S(O)_tR^a(wherein t is 1 or 2) ,-S (O)_tOR^a(wherein t is 1 or 2) ,-S (O)_tR^a(wherein t is 1 or 2) and-S (O)_tN(R^a)₂(wherein t is 1 or 2), wherein each R^aSolely Be on the spot hydrogen, alkyl, fluoroalkyl, carbocylic radical, carbocylic radical alkyl, aryl, aralkyl, heterocyclic radical, cycloheteroalkylalkyl, heteroaryl or Heteroaryl alkyl.

" alkoxy " refers to the group of the oxygen atoms bond by formula-O- alkyl, and wherein alkyl is as defined above Alkyl chain.

" alkenyl " refer to it is being individually made up of carbon atom and hydrogen atom, comprising at least one carbon-to-carbon double bond and have There is straight chain or side chain the hydrocarbon chain radical of the carbon atom from two to 12.In certain embodiments, alkenyl includes two To eight carbon atoms.In other embodiments, alkenyl includes two to four carbon atom.Alkenyl is attached to point by singly-bound The remainder of son, such as vinyl (ethenyl) (that is, vinyl (vinyl)), propyl- 1- alkenyls (that is, pi-allyl), butyl- 1- Alkenyl, amyl- 1- alkenyls, amyl- 1,4- dialkylenes and similar alkenyl.Unless specifically stated in addition in this manual, otherwise alkene Base group is optionally replaced by the one or more in following substituent：Halogen, cyano group, nitro, oxo, thio, imino group, Oximido, trimethylsilyl ,-OR^a、-SR^a、-OC(O)-R^a、-N(R^a)₂、-C(O)R^a、-C(O)OR^a、-C(O)N(R^a)₂、-N (R^a)C(O)OR^a、-OC(O)-N(R^a)₂、-N(R^a)C(O)R^a、-N(R^a)S(O)_tR^a(wherein t is 1 or 2) ,-S (O)_tOR^a(wherein t Be 1 or 2) ,-S (O)_tR^a(wherein t is 1 or 2) and-S (O)_tN(R^a)₂(wherein t is 1 or 2), wherein each R^aBe independently hydrogen, Alkyl, fluoroalkyl, carbocylic radical, carbocylic radical alkyl, aryl, aralkyl, heterocyclic radical, cycloheteroalkylalkyl, heteroaryl or heteroaryl alkane Base.

" alkynyl " refer to it is being individually made up of carbon atom and hydrogen atom, comprising at least one carbon-to-carbon triple bond, with from Straight chain or side chain the hydrocarbon chain radical of two to 12 carbon atoms.In certain embodiments, alkynyl includes two to eight Individual carbon atom.In other embodiments, alkynyl has two to four carbon atom.Alkynyl is attached to molecule by singly-bound Remainder, such as acetenyl, propinyl, butynyl, pentynyl, hexin base and similar alkynyl.Unless another in this manual Specifically state outside, otherwise alkynyl group is optionally replaced by the one or more in following substituent：Halogen, cyano group, nitre Base, oxo, thio, imino group, oximido, trimethylsilyl ,-OR^a、-SR^a、-OC(O)-R^a、-N(R^a)₂、-C(O)R^a、-C(O) OR^a、-C(O)N(R^a)₂、-N(R^a)C(O)OR^a、-OC(O)-N(R^a)₂、-N(R^a)C(O)R^a、-N(R^a)S(O)_tR^a(wherein t be 1 or 2)、-S(O)_tOR^a(wherein t is 1 or 2) ,-S (O)_tR^a(wherein t is 1 or 2) and-S (O)_tN(R^a)₂(wherein t is 1 or 2), wherein Each R^aBe independently hydrogen, alkyl, fluoroalkyl, carbocylic radical, carbocylic radical alkyl, aryl, aralkyl, heterocyclic radical, cycloheteroalkylalkyl, Heteroaryl or heteroaryl alkyl.

" alkylidene " or " alkylidene chain " refer to individually being made up of carbon and hydrogen, not comprising degree of unsaturation and with from Straight chain or side chain the bivalent hydrocarbon chain that the remainder of molecule is connected to group of one to 12 carbon atom, such as it is sub- Methyl, ethylidene, propylidene, sub- normal-butyl and similar alkylidene.Alkylidene chain is attached to the remainder of molecule by singly-bound Divide and group is attached to by singly-bound.Alkylidene chain is attached to the remainder of molecule can lead to the point for being attached to group Cross in the alkylidene chain a carbon or by any two carbon in the chain.In certain embodiments, alkylidene bag Containing one to eight carbon atom (for example, C₁-C₈Alkylidene).In other embodiments, alkylidene includes one to five carbon original Son is (for example, C₁-C₅Alkylidene).In other embodiments, alkylidene includes one to four carbon atom (for example, C₁-C₄It is sub- Alkyl).In other embodiments, alkylidene includes one to three carbon atom (for example, C₁-C₃Alkylidene).In other implementations In scheme, alkylidene is comprising one to two carbon atom (for example, C₁-C₂Alkylidene).In other embodiments, alkylidene bag Containing a carbon atom (for example, C₁Alkylidene).In other embodiments, alkylidene comprising five to eight carbon atoms (for example, C₅-C₈Alkylidene).In other embodiments, alkylidene includes two to five carbon atoms (for example, C₂-C₅Alkylidene). In other embodiments, alkylidene is comprising three to five carbon atoms (for example, C₃-C₅Alkylidene).Unless another in this manual Specifically state outside, otherwise alkylidene chain is optionally replaced by the one or more in following substituent：Halogen, cyano group, nitre Base, oxo, thio, imino group, oximido, trimethylsilyl ,-OR^a、-SR^a、-OC(O)-R^a、-N(R^a)₂、-C(O)R^a、-C(O) OR^a、-C(O)N(R^a)₂、-N(R^a)C(O)OR^a、-OC(O)-N(R^a)₂、-N(R^a)C(O)R^a、-N(R^a)S(O)_tR^a(wherein t be 1 or 2)、-S(O)_tOR^a(wherein t is 1 or 2) ,-S (O)_tR^a(wherein t is 1 or 2) and-S (O)_tN(R^a)₂(wherein t is 1 or 2), wherein Each R^aBe independently hydrogen, alkyl, fluoroalkyl, carbocylic radical, carbocylic radical alkyl, aryl, aralkyl, heterocyclic radical, cycloheteroalkylalkyl, Heteroaryl or heteroaryl alkyl.

" aryl " is referred to by the way that hydrogen atom is removed from ring carbon atom derived from aromatic monocyclic or polycyclic Hydrocarbon ring system group.Aromatic monocyclic or polycyclic hydrocarbon ring system only includes hydrogen and the carbon atom from five to 18 Carbon, wherein member ring systems middle ring at least one be completely it is undersaturated, i.e., according to Huckel theory (H ü ckel Theory), it includes ring-type, delocalization (4n+2) pi-electron system.Aryl includes but is not limited to derived from its member ring systems, example Such as the group of benzene, fluorenes, dihydroindene, indenes, naphthane and naphthalene.Unless specifically stated in addition in this manual, otherwise art Language " aryl " or prefix " fragrant (ar-) " (such as in " aralkyl ") mean to include optionally to be independently selected from following one kind Or more plant substituent substitution aromatic yl group：Alkyl, alkenyl, alkynyl, halogen, fluoroalkyl, cyano group, nitro, optionally taken The aryl in generation, the aralkyl being optionally substituted, the arylalkenyl being optionally substituted, the sweet-smelling alkynyl being optionally substituted, optionally Carbocylic radical that ground is substituted, the carbocylic radical alkyl being optionally substituted, the heterocyclic radical that is optionally substituted, it is optionally substituted Cycloheteroalkylalkyl, the heteroaryl being optionally substituted, the heteroaryl alkyl ,-R being optionally substituted^b-OR^a、-R^b-OC(O)- R^a、-R^b-OC(O)-OR^a、-R^b-OC(O)-N(R^a)₂、-R^b-N(R^a)₂、-R^b-C(O)R^a、-R^b-C(O)OR^a、-R^b-C(O)N (R^a)₂、-R^b-O-R^c-C(O)N(R^a)₂、-R^b-N(R^a)C(O)OR^a、-R^b-N(R^a)C(O)R^a、-R^b-N(R^a)S(O)_tR^a(wherein t Be 1 or 2) ,-R^b-S(O)_tR^a(wherein t is 1 or 2) ,-R^b-S(O)_tOR^a(wherein t is 1 or 2) and-R^b-S(O)_tN(R^a)₂(wherein T is 1 or 2), wherein each R^aIt is independently that hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkyl-alkyl, aryl are (optionally a kind of Or more plant halogen group substitution), aralkyl, heterocyclic radical, cycloheteroalkylalkyl, heteroaryl or heteroaryl alkyl, each R^bIt is independent Ground is the alkylidene or alkylidene chain of direct key or straight chain or side chain, and R^cIt is the alkylidene or alkylene of straight chain or side chain Base chain, and wherein unless otherwise instructed, in substituent is above otherwise each unsubstituted.

" aralkyl " refers to formula-R^cThe group of-aryl, wherein R^cThe alkylidene chain being as defined above, such as methylene Base, ethylidene and similar group.The alkylidene chain part of aralkyl is optionally substituted, such as above for alkylidene chain Description.The aryl moiety of aralkyl is optionally substituted, as described in above for aryl.

" arylalkenyl " refers to formula-R^dThe group of-aryl, wherein R^dThe alkenylene chain being as defined above.The virtue of arylalkenyl Base section is optionally substituted, as described in above for aryl.The alkenylene chain part of arylalkenyl is optionally to be taken Generation, as defined above for alkenylene.

" sweet-smelling alkynyl " refers to formula-R^eThe group of-aryl, wherein R^eThe alkynylene chain being as defined above.The virtue of sweet-smelling alkynyl Base section is optionally substituted, as described in above for aryl.The alkynylene chain part of sweet-smelling alkynyl is optionally to be taken Generation, as defined above for alkynylene chain.

" aralkoxy " is referred to by formula-O-R^cThe group of the oxygen atoms bond of-aryl, wherein R^cIt is as defined above Alkylidene chain, such as methylene, ethylidene and similar group.The alkylidene chain part of aralkyl is optionally substituted, As described in above for alkylidene chain.The aryl moiety of aralkyl is optionally substituted, and is such as described above for aryl 's.

" carbocylic radical " refer to it is being individually made up of carbon atom and hydrogen atom, fusion or bridge joint ring body can be included System, with from three to the stabilization of 15 carbon atoms non-aromatic monocyclic or polycyclic alkyl.In some embodiment party In case, carbocylic radical includes three to ten carbon atoms.In other embodiments, carbocylic radical includes five to seven carbon atoms. Carbocylic radical is attached to the remainder of molecule by singly-bound.Carbocylic radical can be saturation, (that is, only comprising C -- C single bond) or Undersaturated (that is, comprising one or more double or triple bonds).Fully saturated carbocylic radical is also known as " cycloalkyl ".It is monocyclic The example of cycloalkyl include, such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl and cyclooctyl.It is undersaturated Carbocylic radical is also known as " cycloalkenyl group ".The example of monocyclic cycloalkenyl group includes, for example cyclopentenyl, cyclohexenyl group, cycloheptenyl, And cyclo-octene base.Polycyclic carbocylic radical includes, such as adamantyl, norborneol alkyl (that is, bicyclic [2.2.1] heptyl), drop Borneol alkenyl, decahydro naphthyl, 7,7- dimethyl-bicyclos [2.2.1] heptyl, and the like.Unless special in addition in this manual Surely state, otherwise term " carbocylic radical ", which means to include optionally to be independently selected from following one or more of substituents, takes The carbocylic radical in generation：Alkyl, alkenyl, alkynyl, halogen, fluoroalkyl, oxo, thio, cyano group, nitro, the aryl being optionally substituted, The aralkyl that is optionally substituted, the arylalkenyl being optionally substituted, the sweet-smelling alkynyl that is optionally substituted, it is optionally substituted Carbocylic radical, the carbocylic radical alkyl being optionally substituted, the heterocyclic radical being optionally substituted, the heterocyclic radical alkane being optionally substituted Base, the heteroaryl being optionally substituted, the heteroaryl alkyl ,-R being optionally substituted^b-OR^a、-R^b-OC(O)-R^a、-R^b-OC (O)-OR^a、-R^b-OC(O)-N(R^a)₂、-R^b-N(R^a)₂、-R^b-C(O)R^a、-R^b-C(O)OR^a、-R^b-C(O)N(R^a)₂、-R^b-O- R^c-C(O)N(R^a)₂、-R^b-N(R^a)C(O)OR^a、-R^b-N(R^a)C(O)R^a、-R^b-N(R^a)S(O)_tR^a(wherein t is 1 or 2) ,-R^b-S (O)_tR^a(wherein t is 1 or 2) ,-R^b-S(O)_tOR^a(wherein t is 1 or 2) and-R^b-S(O)_tN(R^a)₂(wherein t is 1 or 2), wherein Each R^aBe independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heterocyclic radical, cycloheteroalkylalkyl, Heteroaryl or heteroaryl alkyl, each R^bIt is independently the alkylidene or alkylidene chain of direct key or straight chain or side chain, and R^c It is the alkylidene or alkylidene chain of straight chain or side chain, and wherein unless otherwise instructed, it is otherwise each in substituent above It is unsubstituted.

" carbocylic radical alkyl " refers to formula-R^cThe group of-carbocylic radical, wherein R^cThe alkylidene chain being as defined above.Alkylene Base chain and carbocylic radical is as defined above is optionally substituted.

" carbocyclylalkoxy " is referred to by formula-O-R^cThe group of the oxygen atoms bond of-carbocylic radical, wherein R^cIt is as above The alkylidene chain of text definition.Alkylidene chain and carbocylic radical is as defined above is optionally substituted.

" halogen (halo) " or " halogen (halogen) " refers to bromine substituent, chlorine substituent, fluoro substituents or iodine substitution Base.

" fluoroalkyl " refers to the alkyl as defined above replaced by one or more fluorin radicals as defined above Group, such as trifluoromethyl, difluoromethyl, methyl fluoride, 2,2,2- trifluoroethyls, 1- methyl fluoride -2- fluoro ethyls, and the like. What the moieties of fluoroalkyl group can be defined as described above for aromatic yl group is optionally substituted.

" heterocyclic radical " refer to comprising two to 12 carbon atoms and selected from nitrogen, oxygen and sulphur from one to six miscellaneous original The ternary of the stabilization of son is to 18 yuan of non-aromatic ring radicals.Unless specifically stated in addition in this manual, otherwise heterocycle Base group is the member ring systems at monocyclic, bicyclic three rings or Fourth Ring, and these member ring systems can include fusion or bridge joint ring System.Hetero atom in heterocyclyl groups can be optionally oxidized.One or more nitrogen-atoms (if present)s are optional Ground is quaternized.Heterocyclyl groups are partially or even wholly saturations.Heterocyclic radical can be attached to by any atom of ring The remainder of molecule.The example of such heterocyclyl groups includes but is not limited to dioxolane base, thieno [1,3] two Thiophene alkyl, Decahydroisoquinolinpreparation base, imidazolinyl, imidazolidinyl, isothiazole alkyl, isoxazole alkyl, morpholinyl, octahydro indoles Base, octahydro isoindolyl, 2- oxopiperazinyls, 2- oxo-piperidine bases, 2- oxo-pyrrolidines base, oxazole alkyl, piperidyl, piperazine Base, 4- piperidone bases, pyrrolidinyl, pyrazolidinyl, quininuclidinyl, thiazolidinyl, tetrahydrofuran base, trithiane base (trithianyl), THP trtrahydropyranyl, thio-morpholinyl (thiomorpholinyl), thiamorpholinyl (thiamorpholinyl), 1- oxo-thiomorpholins base and 1,1- dioxo-thiomorpholinyls.Unless in this specification In specifically state in addition, otherwise term " heterocyclic radical " means to include optionally to be selected from following one or more of substituents The heterocyclic radical as defined above of substitution：Alkyl, alkenyl, alkynyl, halogen, fluoroalkyl, oxo, thio, cyano group, nitro, optionally Aryl that ground is substituted, the aralkyl being optionally substituted, the arylalkenyl being optionally substituted, the aryne being optionally substituted Base, the carbocylic radical being optionally substituted, the carbocylic radical alkyl being optionally substituted, the heterocyclic radical being optionally substituted, optionally Substituted cycloheteroalkylalkyl, the heteroaryl being optionally substituted, the heteroaryl alkyl ,-R being optionally substituted^b-OR^a、-R^b- OC(O)-R^a、-R^b-OC(O)-OR^a、-R^b-OC(O)-N(R^a)₂、-R^b-N(R^a)₂、-R^b-C(O)R^a、-R^b-C(O)OR^a、-R^b-C(O) N(R^a)₂、-R^b-O-R^c-C(O)N(R^a)₂、-R^b-N(R^a)C(O)OR^a、-R^b-N(R^a)C(O)R^a、-R^b-N(R^a)S(O)_tR^a(wherein t Be 1 or 2) ,-R^b-S(O)_tR^a(wherein t is 1 or 2) ,-R^b-S(O)_tOR^a(wherein t is 1 or 2) and-R^b-S(O)_tN(R^a)₂(wherein T is 1 or 2), wherein each R^aIt is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heterocycle Base, cycloheteroalkylalkyl, heteroaryl or heteroaryl alkyl, each R^bBe independently direct key or straight chain or side chain alkylidene or Alkylidene chain, and R^cIt is the alkylidene or alkylidene chain of straight chain or side chain, and wherein unless otherwise instructed, otherwise above In substituent is each unsubstituted.

" N- heterocyclic radicals " or " heterocyclic radical of N- attachments " refers to comprising at least one nitrogen and is wherein attached heterocyclic radical Point to the remainder of molecule is heterocyclyl groups as defined above by the nitrogen-atoms in heterocyclyl groups.N- is miscellaneous Cyclic groups are optionally substituted, as described in above for heterocyclyl groups.The example of such N- heterocyclyl groups Including but not limited to 1- morpholinyls, 1- piperidyls, 1- piperazinyls, 1- pyrrolidinyls, pyrazolidinyl, imidazolinyl and imidazoles Alkyl.

" C- heterocyclic radicals " or " heterocyclic radical of C- attachments " is referred to comprising at least one hetero atom and wherein by heterocyclic radical The point that group is attached to the remainder of molecule is the heterocyclic radical as defined above by the carbon atom in heterocyclyl groups Group.C- heterocyclyl groups are optionally substituted, as described in above for heterocyclyl groups.Such C- heterocyclic radicals base The example of group includes but is not limited to 2- morpholinyls, 2- or 3- or 4- piperidyls, 2- piperazinyls, 2- or 3- pyrrolidinyls and similar Thing.

" cycloheteroalkylalkyl " refers to formula-R^cThe group of-heterocyclic radical, wherein R^cThe alkylidene chain being as defined above.If Heterocyclic radical is nitrogen heterocycle, then heterocyclic radical is optionally attached to alkyl group at nitrogen-atoms.Heterocyclic-alkyl-group Alkylidene chain is optionally substituted, as defined above for alkylidene chain.The heterocyclyl moieties of heterocyclic-alkyl-group It is optionally substituted, as defined above for heterocyclyl groups.

" heterocyclylalkoxy " is referred to by formula-O-R^cThe group of the oxygen atoms bond of-heterocyclic radical, wherein R^cIt is as above The alkylidene chain of text definition.If heterocyclic radical is nitrogen heterocycle, heterocyclic radical is optionally attached to alkyl at nitrogen-atoms Group.The alkylidene chain of heterocyclylalkoxy groups is optionally substituted, as defined above for alkylidene chain.Heterocycle The heterocyclyl moieties of base alkoxy base are optionally substituted, as defined above for heterocyclyl groups.

" heteroaryl " refer to be derived from comprising two to 17 carbon atoms and selected from nitrogen, oxygen and sulphur from one to Six heteroatomic ternarys to 18 yuan of non-aromatic ring radicals group.As it is used herein, heteroaryl groups can be single Ring, bicyclic, three rings or Fourth Ring member ring systems, wherein at least one of member ring systems middle ring are completely undersaturated, i.e. roots According to Huckel theory, it includes ring-type, delocalization (4n+2) pi-electron system.Heteroaryl includes fusion or bridge joint ring body System.Hetero atom in heteroaryl groups is optionally oxidized.One or more nitrogen-atoms (if present)s are optionally by season Ammonium.Heteroaryl is attached to the remainder of molecule by any atom of ring.The example of heteroaryl includes but is not limited to a word used for translation Heptan is because of base, acridinyl, benzimidazolyl, benzindole base, 1,3- benzodioxole groups, benzofuranyl, benzo Oxazolyl, benzo [d] thiazolyl, diazosulfide base, benzo [b] [1,4] benzodioxepin base (benzo [b] [1,4] Dioxepinyl), benzo [b] [1,4] oxazinyls, 1,4- benzodioxanes base, benzo aphthofurans base, benzoxazolyl, Benzodioxole group, benzene and bioxin base, benzopyranyl, chromene ketone group, benzofuranyl, benzofuran Ketone group, benzothienyl (benzothienyl) (benzothienyl (benzothiophenyl)), benzothiophene are simultaneously [3,2-d] Pyrimidine radicals, BTA base, benzo [4,6] imidazo [1,2-a] pyridine radicals, carbazyl, cinnolines base, cyclopenta [d] are phonetic Piperidinyl (cyclopenta [d] pyrimidinyl), 6,7- dihydro -5H- cyclopentas [4,5] thieno [2,3-d] pyrimidine radicals (6,7-dihydro-5H-cyclopenta [4,5] thieno [2,3-d] pyrimidinyl), 5,6- dihydrobenzos [h] quinoline azoles Quinoline base, 5,6- dihydrobenzos [h] cinnolines base, 6,7- dihydro -5H- benzos [6,7] cycloheptatriene simultaneously [1,2-c] pyridazinyl (6,7- Dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazinyl), dibenzofuran group, dibenzothiophenes base, Furyl, furanonyl, furans simultaneously [3,2-c] pyridine radicals, pungent tetraene of 5,6,7,8,9,10- hexahydro rings simultaneously [d] pyrimidine radicals (5, 6,7,8,9,10-hexahydrocycloocta [d] pyrimidinyl), pungent tetraene of 5,6,7,8,9,10- hexahydro rings simultaneously [d] Pyridazinyl, pungent tetraene of 5,6,7,8,9,10- hexahydro rings simultaneously [d] pyridine radicals, isothiazolyl, imidazole radicals, indazolyl, indyl, Indazolyl, isoindolyl, indoline base, isoindoline base, isoquinolyl, indolizine base, isoxazolyls, 5,8- methylene -5,6, 7,8- tetrahydro quinazolines base, naphthyridines base, 1,6- naphthyridones Ji, oxadiazolyls, 2- oxo azepines Ji, oxazolyls, oxirane Base, 5,6,6a, 7,8,9,10,10a- octahydros benzo [h] quinazolyl, 1- phenyl -1H- pyrrole radicals, phenazinyl, phenothiazinyl, Phenoxazine group, phthalazinyl, pteridyl, purine radicals, pyrrole radicals, pyrazolyl, pyrazolo [3,4-d] pyrimidine radicals, pyridine radicals, pyrido [3,2-d] pyrimidine radicals, pyrido [3,4-d] pyrimidine radicals, pyrazinyl, pyrimidine radicals, pyridazinyl, pyrrole radicals, quinazolyl, quinoxaline Base, quinolyl, isoquinolyl, tetrahydric quinoline group, 5,6,7,8- tetrahydro quinazolines base, 5,6,7,8- tetrahydro benzos [4,5] thiophene And [2,3-d] pyrimidine radicals, 6,7,8,9- tetrahydrochysene -5H- cycloheptatriene simultaneously [4,5] thieno [2,3-d] pyrimidine radicals, 5,6,7,8- tetra- Pyridinium hydroxide simultaneously [4,5-c] pyridazinyl, thiazolyl, thiadiazolyl group, triazolyl, tetrazole radical, triazine radical, thieno [2,3-d] pyrimidine Base, thieno [3,2-d] pyrimidine radicals, thieno [2,3-c] pyridine radicals and thienyl (thiophenyl) (that is, thienyl (thienyl)).Unless specifically stated in addition in this manual, otherwise term " heteroaryl " means to include optionally to be chosen The heteroaryl groups as defined above replaced from following one or more of substituents：Alkyl, alkenyl, alkynyl, halogen, fluorine Alkyl, haloalkenyl group, halo alkynyl, oxo, thio, cyano group, nitro, the aryl that is optionally substituted, it is optionally substituted Aralkyl, the arylalkenyl being optionally substituted, the sweet-smelling alkynyl being optionally substituted, the carbocylic radical being optionally substituted, optionally Substituted carbocylic radical alkyl, the heterocyclic radical being optionally substituted, the cycloheteroalkylalkyl being optionally substituted, it is optionally substituted Heteroaryl, the heteroaryl alkyl ,-R that are optionally substituted^b-OR^a、-R^b-OC(O)-R^a、-R^b-OC(O)-OR^a、-R^b-OC(O)- N(R^a)₂、-R^b-N(R^a)₂、-R^b-C(O)R^a、-R^b-C(O)OR^a、-R^b-C(O)N(R^a)₂、-R^b-O-R^c-C(O)N(R^a)₂、-R^b-N (R^a)C(O)OR^a、-R^b-N(R^a)C(O)R^a、-R^b-N(R^a)S(O)_tR^a(wherein t is 1 or 2) ,-R^b-S(O)_tR^a(wherein t be 1 or 2)、-R^b-S(O)_tOR^a(wherein t is 1 or 2) and-R^b-S(O)_tN(R^a)₂(wherein t is 1 or 2), wherein each R^aBe independently hydrogen, Alkyl, fluoroalkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heterocyclic radical, cycloheteroalkylalkyl, heteroaryl or heteroaryl alkane Base, each R^bIt is independently the alkylidene or alkylidene chain of direct key or straight chain or side chain, and R^cIt is straight chain or side chain Alkylidene or alkylidene chain, and wherein unless otherwise instructed, in substituent are above otherwise each unsubstituted.

" N- heteroaryls " refers to comprising at least one nitrogen and heteroaryl groups is wherein attached to the remainder of molecule The point divided is the heteroaryl groups as defined above by the nitrogen-atoms in heteroaryl groups.N- heteroaryl groups are optional What ground was substituted, as described in above for heteroaryl groups.

" C- heteroaryls " refers to remainder as defined above and that heteroaryl groups are wherein attached to molecule Point be heteroaryl groups by the carbon atom in heteroaryl groups.C- heteroaryl groups are optionally substituted, such as Described above for heteroaryl groups.

" heteroaryl alkyl " refers to formula-R^cThe group of-heteroaryl, wherein R^cThe alkylidene chain being as defined above.If Heteroaryl is nitrogenous heteroaryl, then heteroaryl is optionally attached to alkyl group at nitrogen-atoms.Heteroarylalkyl group Alkylidene chain is optionally substituted, as defined above for alkylidene chain.The heteroaryl moieties of heteroarylalkyl group It is optionally substituted, as defined above for heteroaryl groups.

" heteroarylalkoxy " is referred to by formula-O-R^cThe group of the oxygen atoms bond of-heteroaryl, wherein R^cIt is as above The alkylidene chain of text definition.If heteroaryl is nitrogenous heteroaryl, heteroaryl is optionally attached to alkyl at nitrogen-atoms Group.The alkylidene chain of heteroarylalkoxy group is optionally substituted, as defined above for alkylidene chain.Heteroaryl The heteroaryl moieties of base alkoxy base are optionally substituted, as defined above for heteroaryl groups.

As it is used herein, " carboxylic acid bioisostere " refers to being presented similar to carboxylic moiety physical Matter, the functional group of biological property and/or chemical property or functional moiety.The example of carboxylic acid bioisostere includes but not limited In,

And the like.

Compound disclosed herein can be comprising one or more asymmetric centers and can therefore produce can root According to absolute stereochemical be defined as (R)-or (S)-enantiomter, diastereoisomer and other alloisomerism shapes Formula.Unless otherwise stated, all stereoisomeric forms in any ratio for being otherwise intended to compound disclosed herein are expected by present disclosure.When When compound described herein includes olefinic double bonds, and unless otherwise, otherwise it is intended to, present disclosure includes E geometry Both isomers and Z geometric isomers (for example, cis or trans).Similarly, also attempt to include all possible isomers with And its racemic form and optically pure form, and all tautomeric forms.Term " geometric isomer " refers to alkene The E geometric isomers or Z geometric isomers (for example, cis or trans) of double bond.Term " position isomer " is referred in surrounding The constitutional isomer of thimble, such as around the ortho position of phenyl ring, meta and para-isomer.

" dynamic isomer " refers to that the proton wherein from atom to another atom of identical molecule of molecule is moved Shifting is possible molecule.Provided herein is compound can exist in certain embodiments as dynamic isomer.Wherein In the case of tautomerization is possible, the chemical balance of dynamic isomer there will be.The accurate ratio of dynamic isomer is depended on A number of factors, including physical state, temperature, solvent and pH.Some examples of tautomeric equilibrium include：

" optionally " or " optionally " mean that the event or situation that then describe can occur or can not occur, and anticipate Referring to the description includes the situation that situation and wherein described event or situation when the event or situation generation do not occur.Example Such as, " aryl being optionally substituted " means that aryl can be substituted or can not be substituted and mean that the description includes being taken Both the aryl in generation and aryl without substituent.

" pharmaceutically acceptable salt " includes both acid-addition salts and base addition salts.Substituted pyrrolo- described herein The pharmaceutically acceptable salts of any of pyridine derived compounds be intended to cover any pharmaceutically suitable salt form and All pharmaceutically suitable salt forms.The preferred pharmaceutically acceptable salt of compound described herein is pharmaceutically acceptable Acid-addition salts and pharmaceutically acceptable base addition salts.

" pharmaceutically acceptable acid-addition salts " refer to keeping the biopotency of free alkali and those salt of property, the salt It is not biologically or otherwise unacceptable and is being formed with following inorganic acid：For example hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like.Also including the salt with organic acid formation, exemplified by the organic acid As aliphatic monocarboxylic acid and aliphatic dicarboxylic acid, the alkanoic acid being substituted by phenyl, hydroxyl alkane acid, alkanedioic acid, aromatic acid, Aliphatic acid and aromatic sulphonic acid etc., and including such as acetic acid, trifluoroacetic acid, propionic acid, glycolic, pyruvic acid, grass Acid, maleic acid, malonic acid, butanedioic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, Loprazolam, second Alkyl sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid, and the like.Therefore, exemplary salt includes sulfate, pyrosulfate, hydrogen sulfate Salt, sulphite, bisulfites, nitrate, phosphate, dibasic alkaliine, dihydric phosphate, metaphosphate, pyrophosphate, Chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalates, malonic acid Salt, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chloro benzoate, Methyl benzoic acid salt, dinitro-benzoate, phthalate, benzene sulfonate, toluene fulfonate, phenyl acetate salt, lemon Hydrochlorate, lactate, malate, tartrate, methane sulfonates and the like.It is also contemplated that the salt of amino acid, such as arginine Salt, gluconate and galacturonic hydrochlorate are (see for example, Berge S.M. et al., " Pharmaceutical Salts, " Journal of Pharmaceutical Science,66:1-19 (1997), it is integrally incorporated accordingly by reference with it). The acid-addition salts of alkali compounds can according to known to technical staff methods and techniques by make free alkali form with it is sufficient The desired acid contact of amount is prepared with producing salt.

" pharmaceutically acceptable base addition salts " refer to keeping the biopotency of free acid and those salt of property, the salt It is not unacceptable biologically or otherwise.These salt are made from by inorganic base or organic base added to free acid It is standby.Pharmaceutically acceptable base addition salts can be formed with metal or amine (such as alkali and alkaline earth metal ions or organic amine). Include but is not limited to sodium salt, sylvite, lithium salts, ammonium salt, calcium salt, magnesium salts, molysite, zinc salt, mantoquita, manganese from salt derived from inorganic base Salt, aluminium salt and the like.Include but is not limited to primary amine, secondary amine and tertiary amine from salt derived from organic base, substituted amine (including Naturally occurring substituted amine, cyclammonium and deacidite), such as isopropylamine, trimethylamine, diethylamine, three second Amine, tripropyl amine (TPA), monoethanolamine, diethanol amine, DMAE, 2- DEAE diethylaminoethanols, dicyclohexylamine, bad ammonia Acid, arginine, histidine, caffeine, procaine, N, N- dibenzyl-ethylenediamins, chloroprocanine, Hai Baming (hydrabamine), choline, glycine betaine, ethylenediamine, ethylene aniline, N- methyl glucoses osamine, gucosamine, methyl Portugal The salt of grapes glucosamine, theobromine, purine, piperazine, piperidines, N-ethylpiperidine, many polyimide resins and the like.See above-mentioned Berge etc. People.

As it is used herein, " treatment (treatment) " or " treatment (treating) " or " mitigation " or " mitigate (ameliorating) " is used interchangeably io herein (palliating).These terms refer to being used to obtain Obtain the method that beneficial or desired result includes but is not limited to therapeutic benefit and/or preventative benefit." therapeutic benefit " Mean the potential disorderly elimination or mitigation being treated.Moreover, therapeutic benefit with eradicate or mitigate with it is potential disorderly Disorderly the one or more of relevant physiological signs are realized so that in patients it was observed that improving, although patient may be still By potential disorderly torment.For preventative benefit, composition can be administered in the risk for developing into specific disease Patient or be applied to report disease physiological signs one or more of patients, although the diagnosis of this disease may be not Once made.

" pro-drug " means that instruction can be converted to or change into by solvolysis retouch herein under physiological status The compound for the biologically active cpds stated.Therefore, term " pro-drug " refers to that pharmaceutically acceptable biology is lived The precursor of property compound.Pro-drug can be inactive when being administered to subject, but be converted to activity in vivo Compound, for example, pass through hydrolysis.Prodrug compound usually provides dissolubility, histocompatbility in mammiferous organism Or the advantage of sustained release is (see for example, Bundgard, H., Design of Prodrugs (1985), 7-9 pages, 21-24 Page (Elsevier, Amsterdam).

The discussion of pro-drug is in Higuchi, T. et al., " Pro-drugs as Novel Delivery Systems, " A.C.S.Symposium Series, in volume 14 and in Bioreversible Carriers in Drug Design, editor Edward B.Roche, American Pharmaceutical Association and Pergamon Press, in 1987 It is provided, both of which is fully incorporated herein by quoting.

Term " pro-drug " is also meant to include any carrier being covalently bonded, when such pro-drug is administered to During mammalian subject, carrier release of active compounds in vivo.The pro-drug of reactive compound as described herein Can be by modify (modification) in conventional operation or be cracked into parent active compound in vivo Mode modify and be present in the functional group in reactive compound to prepare.Pro-drug includes wherein hydroxyl, amino or sulfydryl quilt The compound of any group is bonded to, when the pro-drug of reactive compound is administered to mammalian subject, any base Group cracks to form free hydroxyl, free amino or free sulfydryl respectively.The example of pro-drug includes but is not limited to Acetic ester derivative, carbamate derivatives and the benzoate derivatives of alcohol functional group or amine functional group in reactive compound and Analog.In certain embodiments, substituted Pyrrolopyridine derivatives compound described herein passes through aldehyde precursor medicine The vivo oxidation of thing or the equivalent pro-drug precursor of aldehyde (aldehyde-equivalent prodrug precursor) is obtained .As illustrated in below, the equivalent pro-drug precursor of aldehyde changes into aldehyde pro-drug in vivo.The body of aldehyde pro-drug Internal oxidition provides substituted Pyrrolopyridine derivatives compound described herein.The equivalent pro-drug precursor of aldehyde is that aldehyde spreads out Biology, such as imines, hydrazone, oxime or the like.

Substituted Pyrrolopyridine derivatives compound

This document describes the substituted Pyrrolopyridine derivatives compound of inhibition of histone demethylase.These chemical combination Thing and composition comprising these compounds are useful for treating cancer and tumor disease.Compound described herein is therefore Can be useful for treatment prostate cancer, breast cancer, carcinoma of urinary bladder, lung cancer and/or melanoma and similar cancer.

A kind of embodiment provides the compound of the structure with formula (I),

Or its pharmaceutically acceptable salt,

Wherein,

R¹It is hydrogen or alkyl；

R²It is hydrogen, halogen or alkyl；

G isOr

N is 0,1 or 2；

Wherein：

X is-(C₁-C₆) alkylidene-,-O- ,-S- or-NR¹-；And

R⁵It is carbocylic radical, heterocyclic radical, aryl or heteroaryl.

Another embodiment provides the compound or its pharmaceutically acceptable salt of formula (I), wherein R¹It is hydrogen.It is another Plant compound or its pharmaceutically acceptable salt that embodiment provides formula (I), wherein R¹It is alkyl.Another embodiment There is provided the compound or its pharmaceutically acceptable salt of formula (I), wherein R¹It is methyl.

Another embodiment provides the compound or its pharmaceutically acceptable salt of formula (I), wherein R²It is hydrogen.

Another embodiment provides the compound of formula (I) or the chemical combination of its pharmaceutically acceptable salt, wherein formula (I) Thing has formula (Ia)：

Another embodiment provides the compound of formula (I) or the chemical combination of its pharmaceutically acceptable salt, wherein formula (I) Thing has formula (Ib)：

Another embodiment provides the compound or its pharmaceutically acceptable salt of formula (I), wherein R³It is alkyl.Separately A kind of embodiment provides the compound or its pharmaceutically acceptable salt of formula (I), wherein R³It is methyl.Another embodiment party Case provides the compound or its pharmaceutically acceptable salt of formula (I), wherein R³It is the alkyl replaced by least one halogen.

Another embodiment provides the compound or its pharmaceutically acceptable salt of formula (I), wherein R³It is carbocylic radical Alkyl or cycloheteroalkylalkyl.Another embodiment provides the compound or its pharmaceutically acceptable salt of formula (I), wherein R³ Selected from the group consisted of：

Another embodiment provides the compound or its pharmaceutically acceptable salt of formula (I), wherein R⁴It is halogen.Separately A kind of embodiment provides the compound or its pharmaceutically acceptable salt of formula (I), wherein R⁴It is chlorine or fluorine.It is another to implement Scheme provides the compound or its pharmaceutically acceptable salt of formula (I), wherein R⁴It is the alkyl replaced by least one halogen. Another embodiment provides the compound or its pharmaceutically acceptable salt of formula (I), wherein R⁴It is-CF₃。

Another embodiment provides the compound or its pharmaceutically acceptable salt of formula (I), wherein R⁴It is alkoxy. Another embodiment provides the compound or its pharmaceutically acceptable salt of formula (I), wherein R⁴It is methoxyl group.Another reality Apply compound or its pharmaceutically acceptable salt of the scheme there is provided formula (I), wherein R⁴It is the alkane replaced by least one halogen Epoxide.Another embodiment provides the compound or its pharmaceutically acceptable salt of formula (I), wherein R⁴It is-OCF₃。

Another embodiment provides the compound or its pharmaceutically acceptable salt of formula (I), wherein R⁴It is carbocylic radical.

Another embodiment provides the compound or its pharmaceutically acceptable salt of formula (I), wherein R⁴It is heterocyclic radical. Another embodiment provides the compound or its pharmaceutically acceptable salt of formula (I), and wherein heterocyclic radical is selected from by with the following group Into group：

Another embodiment provides the compound or its pharmaceutically acceptable salt of formula (I), wherein R⁴It is X-R⁵.Separately A kind of embodiment provides the compound or its pharmaceutically acceptable salt of formula (I), and wherein X is-O-.Another embodiment There is provided the compound or its pharmaceutically acceptable salt of formula (I), wherein X is-S-.Another embodiment provides formula (I) Compound or its pharmaceutically acceptable salt, wherein X is-NR¹-；And R¹It is methyl.

Another embodiment provides the compound or its pharmaceutically acceptable salt of formula (I), wherein R⁵It is aryl.Separately A kind of embodiment provide formula (I) compound or its pharmaceutically acceptable salt, wherein aryl be optionally by halogen ,- CN, alkyl, alkynyl, alkoxy or the phenyl of carbocylic radical substitution.Another embodiment provides the compound or its medicine of formula (I) Acceptable salt, wherein R on⁵It is heteroaryl.Another embodiment provide formula (I) compound or its can pharmaceutically connect The salt received, wherein heteroaryl are the pyridine radicals optionally replaced by halogen ,-CN, alkyl, alkynyl, alkoxy or carbocylic radical.

A kind of embodiment provides the compound of the structure with formula (II),

Or its pharmaceutically acceptable salt,

Wherein,

R¹It is hydrogen or alkyl；

R²It is hydrogen, halogen or alkyl；

G isOr

N is 0,1 or 2；

Wherein：

X is-(C₁-C₆) alkylidene-,-O- ,-S- or-NR¹-；And

R⁵It is carbocylic radical, heterocyclic radical, aryl or heteroaryl.

Another embodiment provides the compound or its pharmaceutically acceptable salt of formula (II), and wherein G isAnother embodiment provides the compound or its pharmaceutically acceptable salt of formula (II), and wherein G isAnother embodiment provides the compound or its pharmaceutically acceptable salt of formula (II), and wherein G isAnother embodiment provides the compound or its pharmaceutically acceptable salt of formula (II), and wherein G is

Another embodiment provides the compound or its pharmaceutically acceptable salt of formula (II), wherein R⁴It is aryl. Another embodiment provides the compound or its pharmaceutically acceptable salt of formula (II), wherein R⁴It is X-R⁵.It is another to implement Scheme provides the compound or its pharmaceutically acceptable salt of formula (II), wherein R⁴It is X-R⁵；X is-NR¹-；And R⁵It is virtue Base.

In certain embodiments, the compound of formula (I) as disclosed herein has the structure provided in table 1.

Table 1

In a further embodiment, the compound of formula (I) is selected from the compound provided in table 2.

Table 2

The preparation of substituted Pyrrolopyridine derivatives compound

The compound used in reactions described herein according to organic synthesis technology well known by persons skilled in the art from Compound described in commercially available chemicals and/or Chemistry Literature starts to be made." commercially available chemicals " is from standard business Industry source is obtained, including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, bag Include Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire,U.K.)、BDH Inc.(Toronto,Canada)、Bionet(Cornwall,U.K.)、Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co.Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz＆Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemical s, Inc. (Rockville, MD) and Wako Chemicals USA, Inc. (Richmond, VA).

Method known to persons of ordinary skill in the art is recognized by various reference books and database.It is described in detail and closes Into the conjunction of useful reactant in the preparation of compound described herein or the reference for providing the paper for describing the preparation Suitable reference book and monograph includes, for example " Synthetic Organic Chemistry ", John Wiley＆Sons, Inc., New York；S.R.Sandler et al., " Organic Functional Group Preparations ", second edition, Academic Press, New York, 1983；H.O House, " Modern Synthetic Reactions ", second edition, W.A.Banjamin, Inc.Menlo Park, Calif.1972；T.L.Kirchrist, " Heterocyclic Chemistry ", second edition, John Wiley＆Sons, New York, 1992；J.March, " Advanced Organic Chemistry:Reactions, Mechanisms and Structure ", the 4th edition, WileyInterscience, New York, 1992.Synthesis reactant useful in the preparation of compound described herein is described in detail or provides and describes the preparation Paper reference other suitable reference book and monograph include, such as Fuhrhop, J. and Penzlin G. " Organic Synthesis:Concepts, Methods, Starting Materials ", the second revised and enlarged edition (1994) John Wiley&Sons ISBN:3-527-29074-5；Hoffman, R.V. " Organic Chemistry, An Intermediate Text " (1996) Oxford University Press, ISBN 0-19-509618-5；Larock, R.C. “Comprehensive Organic Transformations:A Guide to Functional Group Preparations " second editions (1999) Wiley-VCH, ISBN：0-471-19031-4；March, J. " Advanced Organic Chemistry:The 4th edition (1992) John Wiley＆ of Reactions, Mechanisms, and Structure " Sons, ISBN:0-471-60180-2；Otera, J. (editor) " Modern Carbonyl Chemistry " (2000) Wiley- VCH, ISBN:3-527-29871-1；Patai, S. " the Guide to the Chemistry of of Patai's 1992 Functional Groups”(1992)Interscience ISBN:0-471-93022-9；Solomons, T.W.G. " Organic Chemistry " the 7th edition (2000) John Wiley＆Sons, ISBN:0-471-19095-0；Stowell, J.C., " Intermediate Organic Chemistry " second editions (1993) Wiley-Interscience, ISBN:0- 471-57456-2；“Industrial Organic Chemicals:Starting Materials and Intermediates:An Ullmann's Encyclopedia " (1999) John Wiley＆Sons, ISBN:3-527- 29645-X, in volume 8；" Organic Reactions " (1942-2000) John Wiley＆Sons, in more than volume 55；With And " Chemistry of Functional Groups " John Wiley＆Sons, in volume 73.

Specific and similar reactant can also by by be in most of public library and college library, university library, academic library can CAS (the Chemical Abstract of the American Chemical Society (American Chemical Society) obtained Service) prepare known chemicals index and by online database (American Chemical Society, Washington, D.C., more details can be contacted) recognize.Known in catalogue but be not commercially available chemicals can by customization chemistry Prepared by combination mechanism, many in the chemicals organization of supply of its Plays (for example, listed above those) provides customization Composite service.Ginseng for preparation and the selection of the pharmaceutical salts of substituted Pyrrolopyridine derivatives compound described herein The data of examining is P.H.Sstahl＆C.G.Wermuth " Handbook of Pharmaceutical Salts ", Verlag Helvetica Chimica Acta,Zurich,2002。

Substituted Pyrrolopyridine derivatives compound passes through general synthetic route below described in scheme 1-3 To prepare.

Scheme 1

Reference scheme 1, substituted indazole A is by R₁- X is optionally alkylated, with provide compound B (see Cheung, J.Org.Chem.2003,4093).Compound B is in the presence of base by iodate, to provide compound C.Selectively, compound A is in the presence of base by iodate, to provide compound D.Compound D is by R¹- X is alkylated, to provide compound E (main) and change Compound C (secondary) mixture.

Scheme 2

Reference scheme 2, is deprotected using TMS- acetylene, the subsequent TMS under TBAF under the conditions of Sonigashira, will changed Compound F changes into acetylide G.Compound G and halo-indazole C are converted to chemical combination under Sonigashira coupling conditions Thing H.Compound H is heated in the presence of alkali and copper, to be cyclized into compound J.Compound J is hydrolyzed in the basic conditions, with to Go out compound K.

Scheme 3

Reference scheme 3, is deprotected using TMS- acetylene, the subsequent TMS under TBAF under the conditions of Sonigashira, will changed Compound F changes into acetylide G.Compound G and halo-indazole E are converted to chemical combination under Sonigashira coupling conditions Thing L.Compound L is heated in the presence of alkali and copper, to be cyclized into compound M.Compound M is hydrolyzed in the basic conditions, with to Go out compound N.

Response procedures above or scheme it is each in, various substituents can be each selected from what is otherwise instructed herein Plant substituent.

Pharmaceutical composition

In certain embodiments, the Pyrrolopyridine derivatives compound being substituted as described herein is used as pure change Product are administered.In other embodiments, the Pyrrolopyridine derivatives compound being substituted as described herein is with being based on As for example in Remington:The Science and Practice of Pharmacy (Gennaro, the 21st edition, Mack Pub.Co., Easton, PA (2005)) selection described in (the disclosure of which accordingly by quote be integrally incorporated with it) applies The pharmaceutically suitable or acceptable carrier selected with path and standard pharmaceutical practice (is also known as pharmaceutically herein Suitably (or acceptable) excipient, physiologically suitable (or acceptable) excipient or physiologically it is suitable (or It is acceptable) carrier) combination.

Therefore, there is provided herein pharmaceutical composition, the pharmaceutical composition is comprising at least one substituted as described herein Pyrrolopyridine derivatives compound or its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or N- Oxide and one or more of pharmaceutically acceptable carriers.If the other compositions of carrier and composition be it is compatible and And be harmless to the recipient (that is, subject) of composition, then carrier (or excipient) is acceptable or suitable.

A kind of embodiment provides the compound comprising pharmaceutically acceptable carrier and formula (I) or its and can pharmaceutically connect The pharmaceutical composition for the salt received.

In certain embodiments, the Pyrrolopyridine derivatives compound being substituted as described herein is generally pure , because it contains other organic molecules less than about 5% or less than about 1% or less than about 0.1%, such as closing Into the intermediate or accessory substance of the pollution of one or more middle generations the step of method.

Suitable peroral dosage form includes such as glutoid or soft gelatin, methylcellulose or is easily dissolved in alimentary canal Tablet, pill, pouch (sachet) or the capsule of another suitable material.Suitable non-toxic solid carrier can be used, Its mannitol for including such as pharmaceutical grade, lactose, starch, magnesium stearate, saccharin sodium, talcum, cellulose, glucose, sucrose, carbon Sour magnesium and the like.(see such as Remington:The Science and Practice of Pharmacy (Gennaro, 21st edition Mack Pub.Co., Easton, PA (2005)).

The dosage of composition comprising at least one substituted Pyrrolopyridine derivatives compound as described herein Can be different, this depends on the situation of patient (for example, mankind), the i.e. stage of disease, overall health, age and medical science Art personnel are by the other factors for determining dosage.

Pharmaceutical composition can be to be suitable for being treated (or being prevented) as what is determined by the technical staff of medical domain The mode of disease is administered.Suitable dosage and it is suitable apply duration and frequency of administration by by the situation of such as patient, Such factor of the type and the order of severity of the disease of patient, the particular form of active component and application process is determined. Generally, suitable dosage and therapeutic scheme are to be enough to provide therapeutic benefit and/or preventative benefit (for example, improved clinic As a result, such as frequent complete or partial alleviation or longer without disease (disease-free) and/or total survival The mitigation of rate or severity of symptom) amount provide composition.Optimal dosage can generally use experimental model and/or face Bed is tested to determine.Optimal dosage can depend on body quality, weight or the blood volume of patient.

Oral dose generally can be in the range of from about 1.0mg to about 1000mg, once a day to four times or more times.

Histone demethylase

Chromatin is the DNA and protein that constitute chromosome compound.Histone is chromatinic main protein group Point, serve as the axle (spool) that DNA is wound about.Covalent modification and non-group egg of the change of chromatin Structure by histone White conjugated protein influence.Can be known with the enzyme of some classifications of covalent modification histone at each site.

Protein can be by methylating on the amino group of lysine and arginic guanidino group or in asparagus fern Carboxy methylation carrys out posttranslational modification (post-translationally on propylhomoserin, glutamic acid or on the C- ends of protein modify).Protein methylation after translation has been directed to various kinds of cell process, and such as RNA processing, receptor-mediated signal are passed Lead and cell differentiation.Protein methylation after translation is widely understood to be occurred on histone, it is known that such reaction is by group Protein methyltransferase is catalyzed, and methyl group is transferred to a group egg by ZNFN3A1 from S-adenosylmethionine (SAM) In vain.The known histone methylated various bioprocess of participation, including heterochromatin formation, x-chromosome are inactivated and turned Record regulation (Lachner et al., (2003) J.Cell Sci.116:2117-2124；Margueron et al., (2005) Curr.Opin.Genet.Dev.15:163-176)。

It is histone methylated whether to cause transcriptional activation or resistance different from acetylation generally related to transcriptional activation Suppression depends on the site specifically methylated and the degree methylated (for example, whether specific istone lysine residue is one It is methylating, di-methylation or tri-methylated).However, generally, methylating on H3K9, H3K27 and H4K20 and base Because silence is relevant, and methylating on H3K4, H3K36 and H3K79 is generally relevant with active gene expression.In addition, H3K4 Tri-methylated and di-methylation generally marks the transcription initiation site for the gene actively transcribed, and H3K4 monomethylization is with strengthening Subsequence is related.

" demethylase " or " albumen demethylase " refers to removing at least one from amino acid side chain as mentioned in this article The enzyme of individual methyl group.Some demethylases act on histone, for example, serving as histone H 3 demethylase or H4 demethylations Enzyme.For example, H3 demethylases can make one or more of demethylations in H3K4, H3K9, H3K27, H3K36 and/or H3K79 Change.Selectively, H4 demethylases can make histone H 4 K20 demethylations.Known demethylase can make monomethyl bottom Thing, di-methylation substrate and/or tri-methylated substrate demethylation.Methylated in addition, histone demethylase can be acted on Core histones substrate, mononucleosome substrate, double-core corpusculum substrate and/or oligoneucleosomes substrate, peptide substrates and/or chromatin (for example, in measure based on cell).

It was found that the first lysine demethylase be lysine specific demethylase 1 (LSD1/KDM1), it uses yellow Element makes both the H3K4 or H3K9 of monomethylated and di-methylation demethylations as co-factor.Include Jumonji C (JmjC) the histone demethylase of the second category in domain is predicted, and is taken off when using Form aldehyde release determination method discovery H3K36 It is proved during methylase, it is named as the histone demethylase 1 (JHDM1/KDM2A) for including JmjC domains.

Then, more protein comprising JmjC domains are accredited, and they only can be gathered into by system spot Seven sub-families：JHDM1, JHDM2, JHDM3, JMJD2, JARID, PHF2/PHF8, UTX/UTY and only JmjC domains.

JMJD2 families

The JMJD2 families of protein are known to make the histone of tri-methylated and di-methylation H3-K9 demethylations The family of demethylase, and be first histone being determined three-methyl demethylase.Especially, JMJD2 families are found The ectopic expression of member tempestuously reduces tri-methylated and di-methylation H3-K9 level, while improving monomethylated H3-K9 level, this makes heterochromatin protein 1 (HP1) delocalization and reduces the aggregate level of internal heterochromatin.Jumonji eggs The member of white JMJD2 sub-families includes JMJD2C and its homologue JMJD2A, JMJD2B, JMJD2D and JMJD2E. The common structure feature found in the JMJD2 sub-families of Jumonji albumen include JmjN sequences, JmjC sequences, PHD sequences and Tdr sequences.

JMJD2C, also referred to as GASC1 and KDM4C, it is known that make tri-methylated H3K9 and H3K36 demethylations.Pass through JMJD2C histone demethylation is via the hydroxylating generation depending on iron and α-ketoglutaric acid, wherein α-ketoglutaric acid Carbon dioxide, succinate and high price iron (ferryl) are produced by JMJD2C oxidative deamination, and then high price iron makes to rely Propylhomoserin H3K9 methyl group hydroxylating, release formaldehyde.Known JMJD2C adjusts adipogenic adjust by nuclear receptors PPAR's γ It is whole, and known JMJD2C participates in the adjustment of the self-renewing in embryonic stem cell.

JARID families

As it is used herein, " JARID albumen " is included in JARID1 sub-families (for example, JARID1A albumen, JARID1B Albumen, JARID1C albumen and JARID1D albumen) and JARID2 sub-families in protein, and its homologue.JARID albumen Further description and list can be in Klose et al. (2006) Nature Reviews/Genetics 7:In 715-727 Find.JARID1 families include some conservative domains：JmjN, ARID, JmjC, PHD and C5HC2 zinc finger (zing finger).

JARID1A, also referred to as KDM5A or RBP2, initially as the combination spouse of retinoblastoma (Rb) albumen Body is found.The demethylase that JARID1A is then found as tri-methylated and di-methylation H3K4 works, and Promotion cell growth is had been observed that, while suppressing aging and differentiation.For example, JARID1A is abolished from mouse cell suppresses cell Growth, induction aging and differentiation, and cause the loss of the versatility of embryonic stem cells in vitro.It has been found that JARID1A is in stomach It is over-expressed in cancer, and has been found that the tumour that JARID1A loss is reduced in Murine cancer models occurs.In addition, research It has been proved that the loss of retinoblastoma binding protein white 2 (RBP2) histone demethylase suppresses lacking Rb1 or Men1 Mouse in tumour occur (Lin et al. Proc.Natl.Acad.Sci.USA, on August 16th, 2011,108 (33), 13379- 86；doi:10.1073/pnas.1110104108), and it is concluded that RBP2 suppressive drugs there will be active anticancer.

JARID1B, also referred to as KDM5B and PLU1, are initially having found by the reality of the gene of HER2 tyrosine-kinase enzyme adjustments It is found in testing.As one man, it has been found that JARID1B is expressed in breast cancer cell line, although in addition to testis just JARID1B limitation is had been found that in normal adult tissue.In addition, 90% invasive ductal carcinoma (invasive ductal Carcinoma expression JARID1B) is had been observed that.Further, it is found that JARID1B is raised in prostate cancer, and benign There is more limited expression in prostate, and have also been discovered that upper in carcinoma of urinary bladder and lung cancer (both SCLC and NSCLC) Adjust.It also have been discovered that JARID1B prevents tumor suppressor gene such as BRCA1, CAV1 and 14-3-3 σ, and it was found that JARID1B's Knock out tri-methylated H3K4 of the increase at these genes level.

In a further embodiment be method for inhibition of histone-demethylase, methods described includes making group Albumen demethylase is contacted with the compound or its pharmaceutically acceptable salt of formula (I).

In a further embodiment be method for inhibition of histone-demethylase, wherein histone-demethylation Enzyme includes JmjC domains.In a further embodiment be method for inhibition of histone-demethylase, wherein histone- Demethylase is JMJD2C.

Treatment method

Disclosed herein is generally or in one or more of specific target genes regulation cell or in subject The method of demethylation.Demethylation can be adjusted to control various cell functions, included, but are not limited to：Differentiation；Propagation；Wither Die；Tumour occurs, leukaemia occurs or other oncogenic transformation events；Alopecia；Or Sex Differentiation.For example, in specific embodiment party In case, the invention provides by adjusting the demethylase comprising JmjC domains (for example, histone demethylase, such as JMJD2C Albumen) activity treat the side of the disease adjusted in its subject is needed by histone methylated and/or demethylation Method.

In a further embodiment be for treat need its subject in cancer method, methods described Including applying the compound comprising formula (I) or the composition of its pharmaceutically acceptable salt to subject.

In a further embodiment be method for treating the cancer in subject, wherein cancer is selected from prostate Cancer, breast cancer, carcinoma of urinary bladder, lung cancer or melanoma.

In a further embodiment be method for suppressing the growth of tumour, methods described, which includes applying, includes formula (I) compound or the composition of its pharmaceutically acceptable salt, wherein tumour are characterized in retinoblastoma gene (RB1) work(loss of energy.

In a further embodiment be method for suppressing the growth of tumour, methods described, which includes applying, includes formula (I) compound or the composition of its pharmaceutically acceptable salt, wherein tumour are characterized in the type gene of Multiple Endocrine knurl 1 (gene of multiple endocrine neoplasia type 1) (Men1) work(loss of energy.

According to present disclosure, other embodiments and purposes will be apparent to those of ordinary skill in the art.Provide Following examples, as just the explanation of various embodiments, and are not necessarily to be construed as limiting the present invention in any way.

Embodiment

I. chemical synthesis

Unless in addition explain, otherwise reagent and solvent such as from commercial supplier arrival when used.Anhydrous solvent and baking The glassware that case is dried is used for the conversion of the synthesis to moisture and/or oxygen sensitive.Yield is not optimised.Reaction time is near As, and it is not optimised.Column chromatography and thin-layered chromatography (TLC) are carried out on silica gel, unless explained in addition.Spectrum with Ppm (δ) is provided and coupling constant J is reported with hertz.For proton spectra, solvent peak is used as reference peak.

Prepare 1a：3- amino -2- ethynyl pyridine -4- carboxylate methyl esters

By 3- Amino-2-Chloropyridine -4- carboxylate methyl esters (1.86g, 10mmol), TMS- acetylene (1.18g, 12mmol), Pd (PPh₃)₂Cl₂(350mg, 0.50mmol), CuI (48mg, 0.25mmol), TEA (5.05g, 50mmol) and acetonitrile (50mL) Mixture is purged with nitrogen, and is stirred overnight at 40 DEG C.Solvent is removed and residue is dissolved in dichloromethane And filter.Filtrate is concentrated and is re-dissolved in THF (10mL).Mixture is cooled to 0 DEG C and dropwise added TBAF (1M, 0.35mL), and reaction is stirred 30 minutes.Mixture is concentrated and passes through silica gel chromatography (PE/EA= 10/1 to 5/1) purify, the title compound of the 1.1g (62%) to provide as yellow solid.For C₉H₈N₂O₂[M+H] Calculated value is 177；Measured value is 177.

Prepare 1b：The iodo- 6- methoxyl groups -2- methyl -2H- indazoles of 3-

KOH is added to mixture of the 6- methoxyl group -2- methyl -2H- indazoles (900mg, 5.55mmol) in DMF (30mL) (1.25g, 22.2mmol), is then added batch-wise I₂(3.0g,22mmol).Reaction is allowed to be stirred at room temperature lasting 16 hours. After completion, by reaction NaHCO₃(saturation, 20mL) is quenched, and content is extracted with ethyl acetate (30mL). By organic matter salt water washing, through Na₂SO₄Dry and concentrate in a vacuum.Residue is passed through into silica flash chromatography (PE/ EA=2/1) purify, the title compound of the 1.19g (74%) to provide as yellow solid.For C₉H₉IN₂O [M+H] meter Calculation value is 289；Measured value is 289.

Prepare 1c：3- amino -2- [2- (6- methoxyl group -2- methyl -2H- indazole -3- bases) acetenyl] Pyridine-4-carboxylic acid first Ester

Will be loaded with iodo- 6- methoxyl groups -2- methyl -2H- indazoles (432mg, 1.50mmol) of 3- in acetonitrile (10mL), 3- amino -2- ethynyl pyridine -4- carboxylate methyl esters (264mg, 1.50mmol), Pd (PPh₃)₂Cl₂(53mg,0.075mmol)、 CuI (8mg, 0.04mmol) and TEA (2ml) round-bottomed flask nitrogen purging continue 2 minutes, and allow to stir at 40 DEG C Continue 16 hours.Reaction is filtered and concentrates filtrate in a vacuum.Residue is passed through into silica gel chromatography (PE/EA=1/ 2) 154mg (30%) of the purifying to provide as brown solid title compound.For C₁₈H₁₆N₄O₃[M+H] calculated value be 337；Measured value is 337.

Prepare 1d：2- (6- methoxyl group -2- methyl -2H- indazole -3- bases) -1H- pyrrolo-es [3,2-b] pyridine-7-carboxylic acid first Ester

It will be loaded with 3- amino -2- [2- (6- methoxyl group -2- methyl -2H- indazole -3- bases) acetylene in DMF (10mL) Base] Pyridine-4-carboxylic acid methyl esters (154mg, 0.458mmol), CaCO₃(46mg, 0.46mmol) and CuI (22mg, 0.11mmol) Round-bottomed flask purged with nitrogen, and at 120 DEG C stirring continue 12 hours.Reaction is concentrated in a vacuum, and will be residual (take up) is in dichloromethane and filters for excess dissolving.Filtrate is concentrated in a vacuum and pure by preparation HPLC Change, the title compound of the 20mg (13%) to provide as yellow solid.For C₁₈H₁₆N₄O₃[M+H] calculated value be 337； Measured value is 337.

Embodiment 1：2- (6- methoxyl group -2- methyl -2H- indazole -3- bases) -1H- pyrrolo-es [3,2-b] pyridine-7-carboxylic acid

It is mounted with 2- (6- methoxyl group -2- methyl -2H- indazole -3- bases) -1H- pyrrolo-es [3,2-b] in THF (1mL) Pyridine-7-carboxylic acid methyl esters (20mg, 0.059mmol), LiOHH₂O (5mg, 0.12mmol) and water (1mL) round-bottomed flask quilt Allow to be stirred at room temperature lasting 3 hours.PH is filtered with HCl (1N) regulations to 6~7, and by sediment.Solid is used two Chloromethanes is washed and dried, the title compound of the 13mg (68%) to provide as orange solids.¹H NMR(300MHz, DMSO-d₆):δ 4.11 (3H, s), 4.25 (3H, s), 7.23 (1H, J=9.3Hz, d), 7.50-7.53 (2H, m), 7.83 (1H, J =9.0Hz, d), 8.45-8.49 (2H, m), 12.79 (1H, s).LCMS (mobile phases：10%-95% acetonitrile-waters -0.02% NH₄Ac)：Purity is>95%, Rt=2.804min.For C₁₇H₁₄N₄O₃[M+H] calculated value be 323；Measured value is 323.

Prepare 2a：5- methoxyl group -2- methyl -2H- indazoles

BF is added to solution of the 5- methoxy-indazoles (1.0g, 6.7mmol) in ethyl acetate (10mL)₄O(CH₃)₃ (1.3g,8.9mmol).Solution is stirred at room temperature lasting 3 hours.Add the NaHCO of saturation₃The aqueous solution (10ml) and use Ethyl acetate (20ml) is extracted.By organic matter through Na₂SO₄Dry, concentration, and pass through silica flash chromatography (PE/EA=2: 1) purify, the title compound of the 0.64g (59%) to provide as yellow solid.For C₉H₁₀N₂O [M+H] calculated value is 163；Measured value is 163.

Prepare 2b：The iodo- 5- methoxyl groups -2- methyl -2H- indazoles of 3-

Title compound is made according to the program for preparing 1b from 5- methoxyl group -2- methyl -2H- indazoles with 70% yield It is standby.For C₉H₉IN₂O [M+H] calculated value is 289；Measured value is 289.

Embodiment 2：2- (5- methoxyl group -2- methyl -2H- indazole -3- bases) -1H- pyrrolo-es [3,2-b] pyridine-7-carboxylic acid

Title compound sequentially (prepares 1c, prepare 1d, embodiment 1) from preparation according to the program for preparing embodiment 1 2b starting with<It is prepared by 10% total recovery.¹H NMR(300MHz,DMSO-d₆):δ3.78(3H,s),4.22(3H,s),6.97- 7.01(2H,m),7.12(1H,s),7.59-7.63(2H,m),8.55-8.57(1H,m),11.62(1H,s).LCMS (flowings Phase：5%-95% acetonitrile-waters -0.02%TFA)：Purity is>95%, Rt=2.853min.For C₁₇H₁₄N₄O₃[M+H] meter Calculation value is 323；Measured value is 323.

Prepare 3a：3- amino -2- [2- (6- chloro-2-methyl -2H- indazole -3- bases) acetenyl] Pyridine-4-carboxylic acid methyl esters

By 3- amino -2- ethynyl pyridine -4- carboxylate methyl esters (176mg, 1mmol), the iodo- 2- methyl -2H- Yin of the chloro- 3- of 6- Azoles (1mmol), Pd (ACN)₂Cl₂(7mg, 0.025mmol), xphos (24mg, 0.05mmol), K₂CO₃(552mg, 4mmol) and The mixture of acetonitrile (10mL) is purged with nitrogen and is stirred overnight at 80 DEG C.By reaction filtering, and by filtrate concentration simultaneously And purified by silica gel chromatography (PE/EA=5/1~2/1), the 300mg's (88%) to provide as yellow solid is titled Compound.For C₁₇H₁₃ClN₄O₂[M+H] calculated value be 341；Measured value is 341.

Prepare 3b：2- (6- chloro-2-methyl -2H- indazole -3- bases) -1H- pyrrolo-es [3,2-b] pyridine-7-carboxylic acid methyl esters

3a (170mg, 0.5mmol), CaCO will be prepared₃(100mg, 1mmol), CuI (24mg, 0.125mmol) and DMF The mixture of (10mL) is purged with nitrogen, and stirring continues 1 hour at 120 DEG C.Solvent is removed, and residue is molten Solution is in dichloromethane and filters.Filtrate is concentrated and purified by preparation HPLC, to provide the mark of 65mg (38%) Inscribe compound.¹H NMR(400MHz,DMSO-d₆):δ3.99(3H,s),4.27(3H,s),7.15-7.21(2H,m),7.70- 7.82 (3H, m), 8.62 (1H, d, J=4.8Hz), 11.86 (1H, br s).LCMS (mobile phases：5%-95% acetonitrile-waters- 0.02%NH₄Ac)：Purity is>95%, Rt=3.930min.For C₁₇H₁₃ClN₄O₂[M+H] calculated value be 341；Measured value For 341.

Embodiment 3：2- (6- chloro-2-methyl -2H- indazole -3- bases) -1H- pyrrolo-es [3,2-b] pyridine-7-carboxylic acid

The mixture of 3b (0.16mmol) and NaOH (14mg, 0.35mmol) in methanol (1mL) and water (1mL) will be prepared Heating and continuous 15 minutes at 60 DEG C.Solution is cooled to room temperature, and adjusted pH to 3~4 with 1N HCl/waters solution.Will production Raw sediment washs to collect and be dried under vacuum to provide the title compound of 20mg (60%) by filtering, with DCM Thing.¹H NMR(400MHz,DMSO-d₆):δ4.27(3H,s),7.15-7.19(2H,m),7.68-7.80(3H,m),8.60(1H, s),11.82(1H,br).LCMS (mobile phases：5%-95% acetonitrile-waters -0.02%NH₄Ac)：Purity is>95%, Rt= 2.482min.For C₁₆H₁₁ClN₄O₂[M+H] calculated value be 327；Measured value is 327.

Prepare 4a：3- amino -2- { 2- [2- methyl -5- (trifluoromethyl) -2H- indazole -3- bases] acetenyl } pyridine -4- carboxylics Sour methyl esters

Title compound according to for prepare 3a program from iodo- 2- methyl -5- (the trifluoromethyl) -2H- indazoles of 3- with It is prepared by 85% yield.For C₁₈H₁₃F₃N₄O₂[M+H] calculated value be 375；Measured value is 375.

Prepare 4b：2- [2- methyl -5- (trifluoromethyl) -2H- indazole -3- bases] -1H- pyrrolo-es [3,2-b] pyridine -7- carboxylics Sour methyl esters

Title compound is prepared according to the program for preparing 3b from 4a is prepared with 43% yield.¹H NMR(300MHz, DMSO-d₆):δ4.01(3H,s),4.32(3H,s),7.30(1H,s),7.55-7.59(1H,m),7.71-7.73(1H,m), 7.93 (1H, d, J=9.3Hz), 8.10 (1H, s), 8.62-8.64 (1H, m), 11.97 (1H, s).LCMS (mobile phases：10%- 95% acetonitrile-water -0.02%NH₄Ac)：Purity is>95%, Rt=3.766min.For C₁₈H₁₃F₃N₄O₂[M+H] calculated value For 375；Measured value is 375.

Embodiment 4：2- [2- methyl -5- (trifluoromethyl) -2H- indazole -3- bases] -1H- pyrrolo-es [3,2-b] pyridine -7- Carboxylic acid

Title compound is prepared according to the program for embodiment 3 from 4b is prepared with 70% yield.¹H NMR (400MHz,DMSO-d₆):δ 4.31 (3H, s), 7.26 (1H, s), 7.56 (1H, d, J=9.2Hz), 7.68 (1H, d, J= 4.8Hz), 7.91 (1H, d, J=9.2Hz), 8.09 (1H, s), 8.59-8.63 (1H, m), 11.91 (1H, s), 13.81 (1H, br).LCMS (mobile phases：10%-95% acetonitrile-waters -0.02%NH₄Ac)：Purity is>95%, Rt=2.371min.For C₁₇H₁₁F₃N₄O₂[M+H] calculated value be 361；Measured value is 361.

Prepare 5a：3- amino -2- { 2- [2- methyl -5- (trifluoromethoxy) -2H- indazole -3- bases] acetenyl } pyridine -4- Carboxylate methyl ester

Title compound according to for prepare 3a program from iodo- 2- methyl -5- (the trifluoromethoxy) -2H- indazoles of 3- with It is prepared by 79% yield.For C₁₈H₁₃F₃N₄O₃[M+H] calculated value be 391；Measured value is 391.

Prepare 5b：2- [2- methyl -5- (trifluoromethoxy) -2H- indazole -3- bases] -1H- pyrrolo-es [3,2-b] pyridine -7- Carboxylate methyl ester

Title compound is prepared according to the program for preparing 3b from 5a is prepared with 66% yield.¹H NMR(400MHz, DMSO-d₆):δ3.99(3H,s),4.29(3H,s),7.22(1H,s),7.32-7.34(1H,m),7.63(1H,s),7.71 (1H, d, J=4.4Hz), 7.86 (1H, d, J=9.2Hz), 8.62 (1H, d, J=4.8Hz), 11.86 (1H, s).LCMS (flowings Phase：10%-95% acetonitrile-waters -0.02%NH₄Ac)：Purity is>95%, Rt=3.857min.For C₁₈H₁₃F₃N₄O₃[M+ H] calculated value be 391；Measured value is 391.

Embodiment 5：2- [2- methyl -5- (trifluoromethoxy) -2H- indazole -3- bases] -1H- pyrrolo-es [3,2-b] pyridine - 7- carboxylic acids

Title compound is prepared according to the program for embodiment 3 from 5b is prepared with 88% yield.¹H NMR (400MHz,DMSO-d₆):δ4.29(3H,s),7.19(1H,s),7.31-7.33(1H,m),7.63-7.68(2H,m),7.84 (1H, d, J=9.2Hz), 8.60 (1H, d, J=4.8Hz), 11.82 (1H, s), 13.83 (1H, br s).LCMS (mobile phases： 5%-95% acetonitrile-waters -0.02%NH₄Ac)：Purity is>95%, Rt=2.610min.For C₁₇H₁₁F₃N₄O₃[M+H] meter Calculation value is 377；Measured value is 377.

Prepare 6a：3- amino -2- [2- (5- cyclopropyl -2- methyl -2H- indazole -3- bases) acetenyl] Pyridine-4-carboxylic acid first Ester

Title compound is received according to the program for preparing 3a from the iodo- 2- methyl -2H- indazoles of 5- cyclopropyl -3- with 81% It is prepared by rate.For C₂₀H₁₈N₄O₂[M+H] calculated value be 347；Measured value is 347.

Prepare 6b：2- (5- cyclopropyl -2- methyl -2H- indazole -3- bases) -1H- pyrrolo-es [3,2-b] pyridine-7-carboxylic acid first Ester

Title compound is prepared according to the program for preparing 3b from 6a is prepared with 40% yield.¹H NMR(400MHz, CDCl₃):δ0.76-0.78(2H,m),0.98-1.02(2H,m),2.02-2.04(1H,m),4.08(3H,s),4.37(3H, S), 7.06-7.13 (2H, m), 7.12 (1H, s), 7.52 (1H, s), 7.66-7.71 (1H, m), 8.66 (1H, d, J=4.8Hz), 9.94(1H,s).LCMS (mobile phases：5%-95% acetonitrile-waters -0.02%NH₄Ac)：Purity is>95%, Rt=3.972min. For C₂₀H₁₈N₄O₂[M+H] calculated value be 347；Measured value is 347.

Embodiment 6：2- (5- cyclopropyl -2- methyl -2H- indazole -3- bases) -1H- pyrrolo-es [3,2-b] pyridine-7-carboxylic acid

Title compound is prepared according to the program for embodiment 3 from 6b is prepared with 85% yield.¹H NMR (400MHz,DMSO-d₆):δ0.69-0.71(2H,m),0.91-0.94(2H,m),2.01-2.04(1H,m),4.24(3H,s), 7.04-7.12 (2H, m), 7.41 (1H, s), 7.57-7.65 (2H, m), 8.57 (1H, d, J=5.2Hz), 11.64 (1H, s), 13.76(1H,br s).LCMS (mobile phases：5%-95% acetonitrile-waters -0.02%NH₄Ac)：Purity is>95%, Rt= 2.612min.For C₁₉H₁₆N₄O₂[M+H] calculated value be 333；Measured value is 333.

Embodiment 7：2- (5- chloro-2-methyl -2H- indazole -3- bases) -1H- pyrrolo-es [3,2-b] pyridine-7-carboxylic acid

Title compound is chloro- from 6- according to the program order (preparing 1c, prepare 1d, embodiment 1) for preparing embodiment 1 The starting of 3- iodo- 2- methyl -2H- indazoles with<It is prepared by 10% total recovery.¹H NMR(400MHz,DMSO-d₆):δ4.36(3H,s), 6.66 (1H, s), 7.06 (1H, d, J=4.6Hz), 7.18 (1H, dd, J=8.9,2.1Hz), 7.57 (1H, d, J=8.9Hz), 7.89 (1H, s), 7.92 (1H, d, J=4.6Hz).For C₁₆H₁₁ClN₄O₂[M+H] calculated value be 327；Measured value is 327.

Prepare 8a：The iodo- 1H- indazoles of the chloro- 3- of 6-

At 0 DEG C, to the solution of the chloro- indazoles of 6- (3.0g, 20mmol) and KOH (4.2g, 74mmol) in DMF (80mL) Add I₂(10g, 40mmol).Mixture is stirred at room temperature lasting 3 hours.By the Na of reaction saturation₂S₂O₃(30mL) is sudden Go out and extracted with EA (50mL).By organic matter through Na₂SO₄Dry, filtering, and filtrate is concentrated and passes through silica gel chromatograph Method (PE/EA=5/1) is purified, the title compound of the 3.9g (71%) to provide as red solid.For C₇H₄ClIN₂'s [M+H] calculated value is 279；Measured value is 279.

Prepare 8b：The iodo- 1H- indazoles of the chloro- 1- ethyls -3- of 6-

Prepare 8c：The iodo- 2H- indazoles of the chloro- 2- ethyls -3- of 6-

By the iodo- 1H- indazoles (1.11g, 4mmol) of the chloro- 3- of 6-, K₂CO₃(1.11g, 8mmol) and iodoethane (1.6mL, 20mmol) mixture in acetonitrile (15mL) is stirred overnight at 80 DEG C.By reaction filtering and filtrate is concentrated and led to Cross silica gel chromatography (PE/EA=1/1) purifying, two kinds of products to provide as yellow solid.

The iodo- 1H- indazoles of the chloro- 1- ethyls -3- of 6- (866mg, 60%)：For C₉H₈ClIN₂[M+H] calculated value be 307； Measured value is 307.

The iodo- 2H- indazoles of the chloro- 2- ethyls -3- of 6- (260mg, 18%)：For C₉H₈ClIN₂[M+H] calculated value be 307； Measured value is 307.

Prepare 8d：3- amino -2- [2- (the chloro- 2- ethyls -2H- indazoles -3- bases of 6-) acetenyl] Pyridine-4-carboxylic acid methyl esters

Title compound is prepared according to the general procedure general introduction for preparing 1c from 8c is prepared with 80% yield.For C₁₈H₁₅ClN₄O₂[M+H] calculated value be 355；Measured value is 355.

Prepare 8e：2- (the chloro- 2- ethyls -2H- indazoles -3- bases of 6-) -1H- pyrrolo-es [3,2-b] pyridine-7-carboxylic acid methyl esters

Title compound is prepared according to the general procedure general introduction for preparing 1d from 8d is prepared with 11% yield.¹H NMR (400MHz,DMSO-d₆):δ 1.57 (3H, J=7.2Hz, t), 4.08 (3H, s), 4.64-4.70 (2H, m), 7.10 (1H, s), 7.17-7.19 (1H, m), 7.72-7.74 (2H, m), 7.84 (1H, d, J=5.2Hz), 8.60 (1H, d, J=4.8Hz).LCMS (mobile phase：5%-95% acetonitrile-waters -0.02%NH₄Ac)：Purity is>95%, Rt=4.144min.For C₁₈H₁₅ClN₄O₂ [M+H] calculated value be 355；Measured value is 355.

Embodiment 8：2- (the chloro- 2- ethyls -2H- indazoles -3- bases of 6-) -1H- pyrrolo-es [3,2-b] pyridine-7-carboxylic acid

Title compound is prepared according to the general procedure general introduction for embodiment 1 from 8e is prepared with 64% yield.¹H NMR(400MHz,DMSO-d₆):δ 1.45 (3H, J=7.2Hz, t), 4.56-4.58 (2H, m), 7.13-7.15 (2H, m), 7.68-7.72 (2H, m), 7.82 (1H, s), 8.62 (1H, J=4.8Hz, d), 11.93 (1H, br s).LCMS (mobile phases： 5%-95% acetonitrile-waters -0.02%NH₄Ac)：Purity is>95%, Rt=2.872min.For C₁₇H₁₃ClN₄O₂[M+H] meter Calculation value is 341；Measured value is 341.

Prepare 9a：The iodo- 1H- indazoles of 6- chloro- 1- (Cvclopropvlmethvl) -3-

Prepare 9b：The iodo- 2H- indazoles of 6- chloro- 2- (Cvclopropvlmethvl) -3-

Title compound is according to for preparing 8b and 8c program from (iodomethyl) cyclopropane and the iodo- 1H- indazoles of the chloro- 3- of 6- To prepare.

The iodo- 1H- indazoles of 6- chloro- 1- (Cvclopropvlmethvl) -3-：(61%).For C₁₁H₁₀ClIN₂[M+H] calculated value be 333；Measured value is 333.

The iodo- 2H- indazoles of 6- chloro- 2- (Cvclopropvlmethvl) -3-：(19%).For C₁₁H₁₀ClIN₂[M+H] calculated value be 333；Measured value is 333.

Prepare 9c：3- amino -2- { 2- [6- chloro- 2- (Cvclopropvlmethvl) -2H- indazole -3- bases] acetenyl } pyridine -4- carboxylics Sour methyl esters

Title compound is prepared according to the general procedure general introduction for preparing 1c from 9b is prepared with 82% yield.For C₂₀H₁₇ClN₄O₂[M+H] calculated value be 381；Measured value is 381.

Prepare 9d：2- [6- chloro- 2- (Cvclopropvlmethvl) -2H- indazole -3- bases] -1H- pyrrolo-es [3,2-b] pyridine -7- carboxylics Sour methyl esters

Title compound is prepared according to the general procedure general introduction for preparing 1b from 9c is prepared with 31% yield.¹H NMR (400MHz,DMSO-d₆):δ0.30-0.32(2H,m),0.54-0.56(2H,m),1.34-1.37(1H,m),4.08(3H,s), 4.51 (2H, J=7.2Hz, d), 7.11 (1H, s), 7.17 (1H, J=8.0Hz, d), 7.71-7.73 (2H, m), 7.84-7.85 (1H,m),8.60(1H,s).LCMS (mobile phases：5%-95% acetonitrile-waters -0.02%NH₄Ac)：Purity is>95%, Rt= 4.238min.For C₂₀H₁₇ClN₄O₂[M+H] calculated value be 381；Measured value is 381.

Embodiment 9：2- [6- chloro- 2- (Cvclopropvlmethvl) -2H- indazole -3- bases] -1H- pyrrolo-es [3,2-b] pyridine -7- Carboxylic acid

Title compound is prepared according to the general procedure general introduction for embodiment 1 from 9d is prepared with 73% yield.¹H NMR(300MHz,DMSO-d₆):δ0.24-0.28(2H,m),0.43-0.47(2H,m),1.24-1.29(1H,m),4.45(2H, J=7.2Hz, d), 7.15-7.19 (2H, m), 7.69-7.74 (2H, m), 7.86 (1H, s), 8.64 (1H, J=5.2Hz), 12.03(1H,br).LCMS (mobile phases：10%-95% acetonitrile-waters -0.02%NH₄Ac)：Purity is>95%, Rt= 2.741min.For C₁₉H₁₅ClN₄O₂[M+H] calculated value be 367；Measured value is 367.

Prepare 10a：The iodo- 1- of the chloro- 3- of 5- [2- (pyrrolidin-1-yl) ethyl] -1H- indazoles

Prepare 10b：The iodo- 2- of the chloro- 3- of 5- [2- (pyrrolidin-1-yl) ethyl] -2H- indazoles

Title compound is according to for preparing 8b and 8c program from 1- (2- chloroethyls) pyrrolidine hydrochlorides and the chloro- 3- of 5- It is prepared by iodo- 1H- indazoles.

The iodo- 1- of the chloro- 3- of 5- [(2- (pyrrolidin-1-yl) ethyl)] -1H- indazoles (39%).For C₁₃H₁₅ClIN₃[M+ H] calculated value be 376；Measured value is 376.

The iodo- 2- of the chloro- 3- of 5- [(2- (pyrrolidin-1-yl) ethyl)] -2H- indazoles (21%).For C₁₃H₁₅ClIN₃[M+ H] calculated value be 376；Measured value is 376.

Prepare 10c：3- amino -2- (2- { the chloro- 2- of 5- [2- (pyrrolidin-1-yl) ethyl] -2H- indazole -3- bases } acetylene Base) Pyridine-4-carboxylic acid methyl esters

Title compound is prepared according to the general procedure general introduction for preparing 1c from 10b is prepared with 69% yield.For C₂₂H₂₂ClN₅O₂[M+H] calculated value be 424；Measured value is 424.

Prepare 10d：2- { the chloro- 2- of 5- [2- (pyrrolidin-1-yl) ethyl] -2H- indazole -3- bases } -1H- pyrrolo-es [3,2- B] pyridine-7-carboxylic acid methyl esters

Title compound is prepared according to the general procedure general introduction for preparing 1d from 10c is prepared with 35% yield.For C₂₂H₂₂ClN₅O₂Calculated value is 424；Measured value is 424.

Embodiment 10：2- { the chloro- 2- of 5- [2- (pyrrolidin-1-yl) ethyl] -2H- indazole -3- bases } -1H- pyrrolo-es [3,2- B] pyridine-7-carboxylic acid

Title compound is prepared according to the general procedure general introduction for embodiment 1 from 10d is prepared with 69% yield.¹H NMR(400MHz,D₂O):δ 1.75 (4H, br s), 2.71 (4H, br s), 3.56 (2H, t, J=6.4Hz), 4.82 (2H, t, J =6.4Hz), 7.24 (1H, s), 7.37 (1H, dd, J=9.0,2.0Hz), 7.67 (1H, d, J=5.1Hz), 7.75-7.81 (2H, m), 8.60 (1H, d, J=4.8Hz).For C₂₁H₂₀ClN₅O₂[M+H] calculated value be 410；Measured value is 410.

Prepare 11a：The bromo- 3- chloro-2-methyls -2H- indazoles of 6-

SO is added to solution of the bromo- 2- methyl -2H- indazoles (1.0g, 4.7mmol) of 6- in AcOH (10mL)₂Cl₂ (0.58mL, 7.1mmol).Solution is stirred at room temperature lasting 4 hours.The 2MNaOH aqueous solution (60mL) is added, and will be anti- Extracted using EA (100mL).By organic matter through Na₂SO₄Dry, concentration, and pass through silica flash chromatography (PE/EA=5/1) Purifying, the title compound of the 1.1g (96%) to provide as yellow solid.For C₈H₆BrClN₂[M+H] calculated value be 245；Measured value is 245.

Prepare 11b：3- chloro- N, 2- dimethyl-N-phenyl -2H- indazole -6- amine

By the bromo- 3- chloro-2-methyls -2H- indazoles (1.0g, 4.10mmol) of 6-, N- metlyl-phenylamines (627mg, 4.10mmol)、Pd₂dba₃(73mg, 0.08mmol), xantphos (138mg, 0.24mmol) and t-BuOK (642mg, 5.74mmol) mixture in toluene (50mL) is purged with nitrogen, and is stirred overnight at 120 DEG C.By reaction filtering simultaneously And concentration.By the purifying of silica gel chromatography (PE/EA=10/1) provide as yellow solid 222mg (20%) it is titled Compound.For C₁₅H₁₄ClN₃[M+H] calculated value be 272；Measured value is 272.

Prepare 11c：3- amino -2- (2- { 2- methyl -6- [methyl (phenyl) amino] -2H- indazole -3- bases } acetenyl) pyrrole Pyridine -4- carboxylate methyl esters

Will prepare 11b (408mg, 1.50mmol), 3- amino -2- ethynyl pyridine -4- carboxylate methyl esters (264mg, 1.50mmol)、Pd(ACN)₂Cl₂(12mg, 0.037mmol), xphos (36mg, 0.075mmol) and K₂CO₃(828mg, 6.00mmol) mixture in acetonitrile (10mL) is purged with nitrogen, and is stirred overnight at 110 DEG C.By reaction filtering, and And filtrate is concentrated and purified by silica gel chromatography (PE/EA=1/2), to provide the 308mg as yellow solid (50%) title compound.For C₂₄H₂₁N₅O₂[M+H] calculated value be 412；Measured value is 412.

Prepare 11d：2- { 2- methyl -6- [methyl (phenyl) amino] -2H- indazole -3- bases } -1H- pyrrolo-es [3,2-b] pyrrole Pyridine -7- carboxylate methyl esters

Title compound is prepared according to the program for preparing 3b from 11c is prepared with 15% yield.For C₂₄H₂₁N₅O₂ [M+H] calculated value be 412；Measured value is 412.

Embodiment 11：2- { 2- methyl -6- [methyl (phenyl) amino] -2H- indazole -3- bases } -1H- pyrrolo-es [3,2-b] Pyridine-7-carboxylic acid

Title compound is prepared according to the general procedure general introduction for embodiment 1 from 11d is prepared with 87% yield.¹H NMR(300MHz,DMSO-d₆):δ3.34(3H,s),4.21(3H,s),6.80-6.84(1H,m),6.90-6.95(1H,m), 6.99-7.02(2H,m),7.07(1H,s),7.15(1H,s),7.24-7.29(2H,m),7.56-7.59(2H,m),8.50 (1H, J=4.8Hz, d), 11.52 (1H, s).LCMS (mobile phases：5%-95% acetonitrile-waters -0.02%TFA)：Purity is> 95%, Rt=3.449min.For C₂₃H₁₉N₅O₂[M+H] calculated value be 398；Measured value is 398.

Prepare 12a：The bromo- 3- chloro-2-methyls -2H- indazoles of 7-

Title compound according to for prepare 11a general procedure from the bromo- 2- methyl -2H- indazoles of 7- with 87% yield come Prepare.For C₈H₆BrClN₂[M+H] calculated value be 245；Measured value is 245.

Prepare 12b：3- chloro- N, 2- dimethyl-N-phenyl -2H- indazole -7- amine

Title compound is prepared according to the general procedure for preparing 11b from 12a is prepared with 29% yield.For C₁₅H₁₄ClN₃[M+H] calculated value be 272；Measured value is 272.

Prepare 12c：3- amino -2- (2- { 2- methyl -7- [methyl (phenyl) amino] -2H- indazole -3- bases } acetenyl) pyrrole Pyridine -4- carboxylate methyl esters

Title compound is prepared according to the general procedure for preparing 11c from 12b is prepared with 37% yield.For C₂₄H₂₁N₅O₂[M+H] calculated value be 412；Measured value is 412.

Prepare 12d：2- { 2- methyl -7- [methyl (phenyl) amino] -2H- indazole -3- bases } -1H- pyrrolo-es [3,2-b] pyrrole Pyridine -7- carboxylate methyl esters

Title compound is prepared according to the program for preparing 3b from 12c is prepared with 20% yield.For C₂₄H₂₁N₅O₂ [M+H] calculated value be 412；Measured value is 412.

Embodiment 12：2- { 2- methyl -7- [methyl (phenyl) amino] -2H- indazole -3- bases } -1H- pyrrolo-es [3,2-b] Pyridine-7-carboxylic acid

Title compound is prepared according to the general procedure general introduction for embodiment 1 from 12d is prepared with 87% yield.¹H NMR(300MHz,DMSO-d₆):δ3.46(3H,s),4.24(3H,s),6.77-6.84(3H,m),7.04-7.21(5H,m), 7.54-7.59 (2H, m), 8.51 (1H, J=4.5Hz, d), 11.56 (1H, s).

LCMS (mobile phases：5%-95% acetonitrile-waters -0.02%NH₄Ac)：Purity is>95%, Rt=3.531min.It is right In C₂₃H₁₉N₅O₂[M+H] calculated value be 398；Measured value is 398.

Prepare 13a：2- (1- methyl isophthalic acid H- indazole -3- bases) -1H- pyrrolo-es [3,2-b] pyridine-7-carboxylic acid methyl esters

By 3- Amino-2-Chloropyridine -4- carboxylate methyl esters (186mg, 1.0mmol), 1- (1- methyl isophthalic acid H- indazole -3- bases) second Ketone (348mg, 2.0mmol), MgSO₄(120mg) and acetic acid (85 μ L, 1.5mmol) merge in DMA (3mL), and will be anti- Mixture nitrogen purging is answered to continue 10 minutes.Add Pd (PtBu₃)₂(50mg, 0.1mmol) and K₃PO₄(276mg, 1.3mmol).Reaction vessel is sealed and heating and continuous 16 hours at 120 DEG C.Reaction is concentrated and passes through preparative HPLC (the 20-65%ACN/ water with 0.1% formic acid) purifying, to provide the title compound of 36mg (12%).For C₁₇H₁₄N₄O₂[M+H] calculated value be 307；Measured value is 307.

Embodiment 13：2- (1- methyl isophthalic acid H- indazole -3- bases) -1H- pyrrolo-es [3,2-b] pyridine-7-carboxylic acid

Title compound is prepared according to the program for embodiment 1 from 13a is prepared with 72% yield.For C₁₆H₁₂N₄O₂ [M+H] calculated value be 293；Measured value is 293.

Embodiment 14：2- (the fluoro- 1- methyl isophthalic acids H- indazoles -3- bases of 5-) -1H- pyrrolo-es [3,2-b] pyridine-7-carboxylic acid

Title compound is fluoro- from 5- according to the program order (preparing 1c, prepare 1d, embodiment 1) for preparing embodiment 1 The starting of 3- iodo- 1- methyl isophthalic acids H- indazoles with<It is prepared by 10% total recovery.¹H NMR(400MHz,DMSO-d₆):δ4.19(3H,s), 7.35-7.45 (3H, m), 7.80 (1H, dd, J=9.1,4.2Hz), 8.04 (1H, d, J=9.2Hz), 8.25-8.32 (2H, m), 11.05(1H,s).LCMS (mobile phases：5%-95% acetonitrile-waters -0.02%TFA)：Purity is>95%, Rt=2.853min. For C₁₆H₁₁FN₄O₂[M+H] calculated value be 311；Measured value is 311.

Prepare 15a：The iodo- 1- methyl isophthalic acids H- indazoles of the chloro- 3- of 6-

Prepare 15d：The iodo- 2- methyl -2H- indazoles of the chloro- 3- of 6-

Title compound is prepared according to the program for being used to prepare 8b and 8c from iodomethane and the iodo- 1H- indazoles of the chloro- 3- of 6-.

The iodo- 1- methyl isophthalic acids H- indazoles of the chloro- 3- of 6-：(61%).For C₈H₆ClIN₂[M+H] calculated value be 293；Measured value For 293.

The iodo- 2- methyl -2H- indazoles of the chloro- 3- of 6-：(22%).For C₈H₆ClIN₂[M+H] calculated value be 293；Measured value For 293.

Prepare 15c：3- amino -2- [2- (the chloro- 1- methyl isophthalic acids H- indazoles -3- bases of 6-) acetenyl] Pyridine-4-carboxylic acid methyl esters

Title compound is prepared according to the general procedure general introduction for preparing 1c from 15a is prepared with 96% yield.For C₁₇H₁₃ClN₄O₂[M+H] calculated value be 341；Measured value is 341.

Prepare 15d：2- (the chloro- 1- methyl isophthalic acids H- indazoles -3- bases of 6-) -1H- pyrrolo-es [3,2-b] pyridine-7-carboxylic acid methyl esters

Title compound is prepared according to the general procedure general introduction for preparing 1d from 15c is prepared with 6% yield.¹H NMR (400MHz,MeOD-d₄):δ4.20(3H,s),4.24(3H,s),7.40-7.46(2H,m),7.85(1H,s),8.03(1H,J =5.6Hz, d), 8.16 (1H, J=8.8Hz, d), 8.64 (1H, J=5.6Hz, d).LCMS (mobile phases：5%-95% acetonitriles- Water -0.02%NH₄Ac)：Purity>95%, Rt=4.388min.For C₁₇H₁₃ClN₄O₂[M+H] calculated value be 341；Actual measurement It is worth for 341.

Embodiment 15：2- (the chloro- 1- methyl isophthalic acids H- indazoles -3- bases of 6-) -1H- pyrrolo-es [3,2-b] pyridine-7-carboxylic acid

Title compound is prepared according to the general procedure general introduction for embodiment 1 from 16d is prepared with 67% yield.¹H NMR(400MHz,DMSO-d₆):δ4.18(3H,s),7.31-7.34(1H,m),7.48-7.50(1H,m),7.61-7.63(1H, m),7.98-8.00(1H,m),8.31-8.33(1H,m),8.53-8.55(1H,m),10.49(1H,br s).LCMS (flowings Phase：10%-95% acetonitrile-waters -0.02%NH₄Ac)：Purity is>95%, Rt=2.952min.For C₁₆H₁₁ClN₄O₂[M+ H] calculated value be 327；Measured value is 327.

Prepare 16a：The iodo- 1- methyl isophthalic acids H- indazoles of the fluoro- 3- of 6-

Prepare 16b：The iodo- 2- methyl -2H- indazoles of the fluoro- 3- of 6-

Title compound is prepared according to the program for being used to prepare 8b and 8c from iodomethane and the iodo- 1H- indazoles of the fluoro- 3- of 6-.

The iodo- 1- methyl isophthalic acids H- indazoles of the fluoro- 3- of 6-：(61%).For C₈H₆FIN₂[M+H] calculated value be 277；Measured value For 277.

The iodo- 2- methyl -2H- indazoles of the fluoro- 3- of 6-：(20%).For C₈H₆FIN₂[M+H] calculated value be 277；Measured value For 277.

Prepare 16c：3- amino -2- [2- (the fluoro- 1- methyl isophthalic acids H- indazoles -3- bases of 6-) acetenyl] Pyridine-4-carboxylic acid methyl esters

Title compound is prepared according to the general procedure general introduction for preparing 1c from 16a is prepared with 90% yield.For C₁₇H₁₃FN₄O₂[M+H] calculated value be 325；Measured value is 325.

Prepare 16d：2- (the fluoro- 1- methyl isophthalic acids H- indazoles -3- bases of 6-) -1H- pyrrolo-es [3,2-b] pyridine-7-carboxylic acid methyl esters

Title compound is prepared according to the general procedure general introduction for preparing 1d from 16c is prepared with 8% yield.¹H NMR (400MHz,DMSO-d₆):δ4.03(3H,s),4.16(3H,s),7.18-7.21(1H,m),7.61-7.70(2H,m),8.29- 8.33(1H,m),8.55-8.58(1H,m),10.75(1H,s).LCMS (mobile phases：5%-95% acetonitrile-waters -0.02% NH₄Ac)：Purity is>95%, Rt=4.150min.For C₁₇H₁₃FN₄O₂[M+H] calculated value be 325；Measured value is 325.

Embodiment 16：2- (the fluoro- 1- methyl isophthalic acids H- indazoles -3- bases of 6-) -1H- pyrrolo-es [3,2-b] pyridine-7-carboxylic acid

Title compound is prepared according to the general procedure general introduction for embodiment 1 from 16d is prepared with 67% yield.¹H NMR(400MHz,DMSO-d₆):δ 4.15 (3H, s), 7.19-7.21 (1H, m), 7.50 (1H, s), 7.59 (1H, J=4.0Hz, D), 7.68 (1H, J=10.4Hz, d), 8.33-8.36 (1H, m), 8.53 (1H, J=4.8Hz, d), 10.42 (1H, br s). LCMS (mobile phases：10%-95% acetonitrile-waters -0.02%NH₄Ac)：Purity is>95%, Rt=2.809min.For C₁₆H₁₁FN₄O₂[M+H] calculated value be 311；Measured value is 311.

Prepare 17a：3- amino -2- [2- (the chloro- 1- ethyls -1H- indazoles -3- bases of 6-) acetenyl] Pyridine-4-carboxylic acid methyl esters

Title compound is prepared according to the general procedure general introduction for preparing 1c from 8b is prepared with 45% yield.For C₁₈H₁₅ClN₄O₂[M+H] calculated value be 355；Measured value is 355.

Prepare 17b：2- (the chloro- 1- ethyls -1H- indazoles -3- bases of 6-) -1H- pyrrolo-es [3,2-b] pyridine-7-carboxylic acid methyl esters

Title compound is prepared according to the general procedure general introduction for preparing 1d from 17a is prepared with 13% yield.¹H NMR(400MHz,MeOD-d₄):δ 1.62 (3H, J=7.2Hz, t), 4.18 (3H, s), 4.61-4.63 (2H, m), 7.39-7.41 (2H, m), 7.85 (1H, s), 7.98 (1H, J=5.6Hz, d), 8.12 (1H, J=4.8Hz, d), 8.61 (1H, J=5.6Hz, d).LCMS (mobile phases：5%-95% acetonitrile-waters -0.02%NH₄Ac)：Purity is>95%, Rt=4.628min.For C₁₈H₁₅ClN₄O₂[M+H] calculated value be 355；Measured value is 355.

Embodiment 17：2- (the chloro- 1- ethyls -1H- indazoles -3- bases of 6-) -1H- pyrrolo-es [3,2-b] pyridine-7-carboxylic acid

Title compound is prepared according to the general procedure general introduction for embodiment 1 from 17b is prepared with 71% yield.¹H NMR(400MHz,DMSO-d₆):δ 1.48 (3H, J=6.8Hz, t), 4.59-4.60 (2H, m), 7.34 (1H, J=8.4Hz, d), 7.50 (1H, s), 7.66 (1H, J=4.4Hz, d), 8.05 (1H, s), 8.31 (1H, J=8.8Hz, d), 8.57 (1H, J= 4.4Hz,d),10.66(1H,br s).LCMS (mobile phases：5%-95% acetonitrile-waters -0.02%NH₄Ac)：Purity is>95%, Rt=3.115min.For C₁₇H₁₃ClN₄O₂[M+H] calculated value be 341；Measured value is 341.

Prepare 18a：3- amino -2- { 2- [6- chloro- 1- (Cvclopropvlmethvl) -1H- indazole -3- bases] acetenyl } pyridine -4- Carboxylate methyl ester

Title compound is prepared according to the general procedure general introduction for preparing 1c from 9a is prepared with 90% yield.For C₂₀H₁₇ClN₄O₂[M+H] calculated value be 381；Measured value is 381.

Prepare 18b：2- [6- chloro- 1- (Cvclopropvlmethvl) -1H- indazole -3- bases] -1H- pyrrolo-es [3,2-b] pyridine -7- Carboxylate methyl ester

Title compound is prepared according to the general procedure general introduction for preparing 1d from 18a is prepared with 16% yield.¹H NMR(400MHz,MeOD-d₄):δ0.52-0.56(2H,m),0.64-0.68(2H,m),1.46-1.48(1H,m),4.11(3H, S), 4.40 (2H, J=7.2Hz, d), 7.28 (1H, s), 7.31-7.33 (1H, m), 7.71-7.77 (2H, m), 8.12 (1H, J= 8.4Hz, d), 8.48 (1H, J=5.2Hz, d).LCMS (mobile phases：5%-95% acetonitrile-waters -0.02%NH₄Ac)：Purity is> 95%, Rt=4.848min.For C₂₀H₁₇ClN₄O₂[M+H] calculated value be 381；Measured value is 381.

Embodiment 18：2- [6- chloro- 1- (Cvclopropvlmethvl) -1H- indazole -3- bases] -1H- pyrrolo-es [3,2-b] pyridine -7- Carboxylic acid

Title compound is prepared according to the general procedure general introduction for embodiment 1 from 18b is prepared with 60% yield.¹H NMR(300MHz,DMSO-d₆):δ 0.47-0.54 (4H, m), 1.38-1.42 (1H, m), 4.46 (2H, J=6.8Hz, d), 7.31-7.34 (1H, m), 7.50 (1H, s), 7.60 (1H, J=4.8Hz, d), 8.08 (1H, s), 8.33 (1H, J=8.8Hz, D), 8.54 (1H, J=4.8Hz, d), 10.45 (1H, br s).LCMS (mobile phases：10%-95% acetonitrile-waters -0.02% NH₄Ac)：Purity is>95%, Rt=3.209min.For C₁₉H₁₅ClN₄O₂[M+H] calculated value be 367；Measured value is 367.

Prepare 19a：The iodo- 1- of the chloro- 3- of 6- (2,2,2- trifluoroethyls) -1H- indazoles

Prepare 19b：The iodo- 2- of the chloro- 3- of 6- (2,2,2- trifluoroethyls) -2H- indazoles

Title compound is iodo- from the fluoro- 2- iodoethane of 1,1,1- tri- and the chloro- 3- of 6- according to the program for preparing 8b and 8c It is prepared by 1H- indazoles.

The iodo- 1- of the chloro- 3- of 6- (2,2,2- trifluoroethyls) -1H- indazoles：(60%).For C₉H₅ClF₃IN₂[M+H] calculate It is worth for 361；Measured value is 361.

The iodo- 2- of the chloro- 3- of 6- (2,2,2- trifluoroethyls) -2H- indazoles：(20%).For C₉H₅ClF₃IN₂[M+H] calculate It is worth for 361；Measured value is 361.

Prepare 19c：3- amino -2- { 2- [the chloro- 1- of 6- (2,2,2- trifluoroethyls) -1H- indazole -3- bases] acetenyl } pyrrole Pyridine -4- carboxylate methyl esters

Title compound is prepared according to the general procedure general introduction for preparing 1c from 19a is prepared with 78% yield.For C₁₈H₁₂ClF₃N₄O₂[M+H] calculated value be 409；Measured value is 409.

Prepare 19d：2- [the chloro- 1- of 6- (2,2,2- trifluoroethyls) -1H- indazole -3- bases] -1H- pyrrolo-es [3,2-b] pyrrole Pyridine -7- carboxylate methyl esters

Title compound is prepared according to the general procedure general introduction for preparing 1d from 19c is prepared with 13% yield.¹H NMR(400MHz,MeOD-d₄):δ4.11(3H,s),5.34-5.41(2H,m),7.35(s,1H),7.39-7.41(1H,m), 7.74 (1H, J=5.2Hz, d), 7.85 (1H, s), 8.17 (1H, J=8.8Hz, d), 8.51 (1H, J=5.2Hz, d).LCMS (mobile phase：5%-95% acetonitrile-waters -0.02%NH₄Ac)：Purity is>95%, Rt=4.583min.For C₁₈H₁₂ClF₃N₄O₂ [M+H] calculated value be 409；Measured value is 409.

Embodiment 19：2- [the chloro- 1- of 6- (2,2,2- trifluoroethyls) -1H- indazole -3- bases] -1H- pyrrolo-es [3,2-b] pyrrole Pyridine -7- carboxylic acids

Title compound is prepared according to the general procedure general introduction for embodiment 1 from 19d is prepared with 74% yield.¹H NMR(300MHz,DMSO-d₆):δ5.64-5.67(2H,m),7.41-7.43(1H,m),7.59-7.64(2H,m),8.17(1H, S), 8.39 (1H, J=8.4Hz, d), 8.57 (1H, J=4.8Hz, d), 10.46 (1H, br s).LCMS (mobile phases：10%- 95% acetonitrile-water -0.02%NH₄Ac)：Purity is>95%, Rt=3.231min.For C₁₇H₁₀ClF₃N₄O₂[M+H] calculate It is worth for 395；Measured value is 395.

Prepare 20a：3- amino -2- (2- { the chloro- 1- of 5- [2- (pyrrolidin-1-yl) ethyl] -1H- indazole -3- bases } acetylene Base) Pyridine-4-carboxylic acid methyl esters

Title compound is prepared according to the general procedure general introduction for preparing 1c from 10a is prepared with 65% yield.For C₂₂H₂₂ClN₅O₂[M+H] calculated value be 424；Measured value is 424.

Prepare 20b：2- { the chloro- 1- of 5- [2- (pyrrolidin-1-yl) ethyl] -1H- indazole -3- bases } -1H- pyrrolo-es [3,2- B] pyridine-7-carboxylic acid methyl esters

Title compound is prepared according to the general procedure general introduction for preparing 1d from 20a is prepared with 39% yield.For C₂₂H₂₂ClN₅O₂Calculated value is 424；Measured value is 424.

Embodiment 20：2- { the chloro- 1- of 5- [2- (pyrrolidin-1-yl) ethyl] -1H- indazole -3- bases } -1H- pyrrolo-es [3,2- B] pyridine-7-carboxylic acid

Title compound is prepared according to the general procedure general introduction for embodiment 1 from 20b is prepared with 66% yield.¹H NMR(400MHz,DMSO-d₆):δ1.91(4H,br s),2.67(4H,br s),3.62-3.77(2H,m),4.91(2H,t,J =6.4Hz), 7.56-7.65 (3H, m), 7.94 (1H, d, J=8.8Hz), 8.42 (1H, s), 8.53 (1H, d, J=4.8Hz), 10.54(1H,s).For C₂₁H₂₀ClN₅O₂[M+H] calculated value be 410；Measured value is 410.

Prepare 21a：3- amino -2- (2- { the fluoro- 1- of 5- [2- (morpholine -4- bases) ethyl] -1H- indazole -3- bases } acetenyl) Pyridine-4-carboxylic acid methyl esters

Title compound is summarized from the iodo- 1- of the fluoro- 3- of 5- [2- (morpholine -4- bases) second according to the general procedure for preparing 1c Base] -1H- indazoles (see U.S. Patent Application Publication 2014/171432) are prepared with 59% yield.For C₂₂H₂₂FN₅O₃[M+ H] calculated value be 424；Measured value is 424.

Prepare 21b：2- { the fluoro- 1- of 5- [2- (morpholine -4- bases) ethyl] -1H- indazole -3- bases } -1H- pyrrolo-es [3,2-b] Pyridine-7-carboxylic acid methyl esters

Title compound is prepared according to the general procedure general introduction for preparing 1d from 21a is prepared with 30% yield.For C₂₂H₂₂FN₅O₃Calculated value is 424；Measured value is 424.

Embodiment 21：2- { the fluoro- 1- of 5- [2- (morpholine -4- bases) ethyl] -1H- indazole -3- bases } -1H- pyrrolo-es [3,2-b] Pyridine-7-carboxylic acid

Title compound is prepared according to the general procedure general introduction for embodiment 1 from 21b is prepared with 68% yield.¹H NMR(400MHz,DMSO-d₆):δ2.67(4H,br s),3.02(2H,br s),3.59(4H,br s),4.76(2H,br s), 7.46 (1H, t, J=8.9Hz), 7.55 (1H, s), 7.61 (1H, s), 7.93 (1H, dd, J=9.2,4.0Hz), 8.12 (1H, d, J=8.9Hz), 8.56 (1H, s).For C₂₁H₂₀FN₅O₃[M+H] calculated value be 410；Measured value is 410.

II. biological assessment

Embodiment 1：External enzyme inhibition assay

This determines the ability for determining that test compound suppresses JMJD2C hepatic Microsomal Aniline Hydroxylases.The JMJD2C of baculovirus expression (GenBank accession number BC143571, AA 2-372) is purchased from BPS Bioscience (article No. 50105).

JMJD2C is determined

The ability that test compound suppresses JMJD2C activity is existed with 384 orifice plate forms (384-well plate format) Following reaction condition gets off determination：Peptide (the Anaspec article No.s of 0.3nM JMJD2C, 300nM H3K9me3- biotin labelings 64360), 2 μM of α-ketoglutaric acids in 50mM HEPES (pH7.3) measure buffer solution, 0.005%Brij35,0.5mM TCEP, 0.2mg/ml BSA, 50 μM of L-AA sodium and 2 μM of ferric sulfate (II) ammoniums.In LANCE detection buffer solutions Detection reagent Phycolink Streptavidins-allophycocyanin is added in the presence of 5mM EDTA (PerkinElmer) (Streptavidin-allophycocyanin) the histone H 3 lysine 9 of (Prozyme) and europium-anti-di-methylation (H3K9me2) antibody (PerkinElmer) to respectively 50nM and 1nM ultimate density after, reaction product by TR-FRET come Quantitatively determine.

Reaction is determined by following to trigger：By the peptide of 900nM H3K9me3- biotin labelings and 6 μM of α -one penta 2 2 μ L of acid mixture is added to each hole of plate together with the inhibitor of the 11- point serial dilutions of the 2 μ L in 3%DMSO, Then 2 μ L of addition 0.9nM JMJD2C are with initiation reaction.Reactant mixture is incubated at room temperature lasting 30 minutes, and led to Addition is crossed in the LANCE inspections comprising 100nM Phycolink Streptavidins-allophycocyanin and 2nM europiums-anti-H3K9me2 antibody The 6 μ L surveyed in buffer solution 5mM EDTA are terminated.After incubating 1 hour at room temperature, plate passes through EnVisionMultilabel Reader (is excited, launch under 615nm and 665nm) at 320nm under TR-FRET patterns and read.Calculated for each hole Ratio (665/615), and be fitted to determine inhibition constant (IC₅₀)。

The ability that pyridine compounds disclosed herein suppress hepatic Microsomal Aniline Hydroxylase is quantified, and determines respective IC₅₀Value. Table 3 provides the IC of various compounds disclosed herein₅₀Value.

The ability that compound disclosed herein suppresses hepatic Microsomal Aniline Hydroxylase is quantified, and determines respective IC₅₀Value.Table 3 There is provided the IC of various compounds disclosed herein₅₀Value.

Table 3

Note：Biochemical measurement IC₅₀Data are specified in following scope：

A:≤0.10μM B:>0.10 μM to≤1.0 μM

C:>1.0 μM to≤10 μM D:>10μM

Embodiment 2：Measure based on cell in vitro

It is that after 168 hours of compound incubation, measurement is urinated via bromine deoxidation that the main cell that JMJD2C suppresses, which is determined, The measure for the cell propagation that glycosides (BrdU) is incorporated to.The cell line of test includes the cell line KYSE-150 of JMJD2C gene magnifications. This is that the quantitative ELISA measure that BrdU DNA is incorporated to is measured during the S- phases, the direct reading result bred as cell.

Measuring principle：This is that the colorimetric immunoassay bred for quantitative cell is determined.Measure is handled with test compound to be continued The cell of 168 hours is used as measuring for its multiplication potentiality by the ability of S- phases.

Assay method：People KYSE-150 (SMAD4mut, TP53mut) esophageal carcinoma cell lines are connect with 2,000 cells/wells Plant on the plate of 96 hole tissue culture treateds.After Overnight incubation, cell is used in, and there is scope to be from 100 μM to 2nM's Compound processing cell in 11 dilution series of ultimate density.Then, cell is incubated in the presence of compound and continued 168 hours.After compound incubation, breed ELISA (Roche) using BrdU cells and determine cell.Cell is used first BrdU labelled reagents, which are incubated, continues 2 hours.After 2 hr, the cell that BrdU is incorporated to is fixed and is denatured, use anti-BrdU- Peroxidase Antibody detection continues 1.5 hours and washed.Finally, by tetramethyl benzidine peroxidase substrate at 15 points Each hole is added in clock, H is then added₂SO₄Stop solution.Plate is read at 450nm, and it is using following formula that original light is close Degrees of data is transformed into XLFit (IDBS), for IC₅₀Calculate：Fit=(D+ ((V_{It is maximum}*(x^n))/((x^n)+(Km^n))))。

Table 4 provides the cell IC of various compounds disclosed herein₅₀Value.

Table 4

Note：Raji cell assay Raji IC₅₀Data are specified in following scope：

A:≤0.10μM B:>0.10 μM to≤1.0 μM

C:>1.0 μM to≤10 μM D:>10μM

Embodiment 3：Internal heterograft research

Time release bead (Time release pellet) containing 0.72mg 17- β estradiol is subcutaneously implanted nu/ In nu mouse.MCF-7 cells are in the RPMI comprising 10%FBS in 5%CO₂, grow at 37 DEG C.Cell is rotated (spin down) and with 1 × 10⁷Individual cell/mL is resuspended in 50%RPMI (serum-free) and 50% matrigel (Matrigel) in.After bead implantation (100 μ L/ animals) is subcutaneously injected on right side in 2-3 days in MCF-7 cells, and two weeks Once (long x is wide for monitoring gross tumor volume²/2).When tumour reaches~200mm³Average external volume when, by animal randomization and start Treatment.Animal is continued 4 weeks with medium or compounds for treating daily.Gross tumor volume and body weight in whole research biweekly Ground is monitored.At the end for the treatment of cycle, blood plasma and tumor sample is taken to carry out pharmacokinetic analysis and pharmacodynamic analysis respectively.

III. the preparation of pharmaceutical dosage form

Embodiment 1：Oral tablet

Tablet is by making the compound or its pharmaceutically acceptable salt, by weight of by weight 48% formula (I) 45% microcrystalline cellulose, by weight 5% low substituted hydroxypropyl cellulose and by weight 2% magnesium stearate are mixed Close to prepare.Tablet is prepared by directly compressing.The gross weight of the tablet of compression is maintained at 250-500mg.

Claims

1. the compound of structure of the one kind with formula (I),

Or its pharmaceutically acceptable salt,

Wherein,

R¹It is hydrogen or alkyl；

R²It is hydrogen, halogen or alkyl；

G is

N is 0,1 or 2；

Wherein：

X is-(C₁-C₆) alkylidene-,-O- ,-S- or-NR¹-；And

R⁵It is carbocylic radical, heterocyclic radical, aryl or heteroaryl.

2. compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein R¹It is hydrogen.

3. compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein R¹It is alkyl.

4. compound as claimed in claim 3 or its pharmaceutically acceptable salt, wherein R¹It is methyl.

5. compound or its pharmaceutically acceptable salt as any one of claim 1-4, wherein R²It is hydrogen.

6. compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein the compound of the formula (I) has formula (Ia)：

7. compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein the compound of the formula (I) has formula (Ib)：

8. compound or its pharmaceutically acceptable salt as any one of claim 1-7, wherein R³It is alkyl.

9. compound as claimed in claim 8 or its pharmaceutically acceptable salt, wherein R³It is methyl.

10. compound or its pharmaceutically acceptable salt as any one of claim 1-7, wherein R³It is by least one The alkyl of individual halogen substitution.

11. compound or its pharmaceutically acceptable salt as any one of claim 1-7, wherein R³It is carbocylic radical alkane Base or cycloheteroalkylalkyl.

12. compound as claimed in claim 11 or its pharmaceutically acceptable salt, wherein R³Selected from the group consisted of：

13. compound or its pharmaceutically acceptable salt as any one of claim 1-12, wherein R⁴It is halogen.

14. compound as claimed in claim 13 or its pharmaceutically acceptable salt, wherein R⁴It is chlorine or fluorine.

15. compound or its pharmaceutically acceptable salt as any one of claim 1-12, wherein R⁴It is by least one The alkyl of individual halogen substitution.

16. compound as claimed in claim 15 or its pharmaceutically acceptable salt, wherein R⁴It is-CF₃。

17. compound or its pharmaceutically acceptable salt as any one of claim 1-12, wherein R⁴It is alkoxy.

18. compound as claimed in claim 17 or its pharmaceutically acceptable salt, wherein R⁴It is methoxyl group.

19. compound or its pharmaceutically acceptable salt as any one of claim 1-12, wherein R⁴It is by least one The alkoxy of individual halogen substitution.

20. compound as claimed in claim 19 or its pharmaceutically acceptable salt, wherein R⁴It is-OCF₃。

21. compound or its pharmaceutically acceptable salt as any one of claim 1-12, wherein R⁴It is carbocylic radical.

22. compound or its pharmaceutically acceptable salt as any one of claim 1-12, wherein R⁴It is heterocyclic radical.

23. compound as claimed in claim 22 or its pharmaceutically acceptable salt, wherein the heterocyclic radical is selected from by following The group of composition：

24. compound or its pharmaceutically acceptable salt as any one of claim 1-12, wherein R⁴It is X-R⁵。

25. compound as claimed in claim 24 or its pharmaceutically acceptable salt, wherein X is-O-.

26. compound as claimed in claim 24 or its pharmaceutically acceptable salt, wherein X is-S-.

27. compound as claimed in claim 24 or its pharmaceutically acceptable salt, wherein X is-NR¹-；And R¹It is methyl.

28. compound or its pharmaceutically acceptable salt as any one of claim 24-27, wherein R⁵It is aryl.

29. compound as claimed in claim 28 or its pharmaceutically acceptable salt, wherein the aryl is optionally by halogen Element ,-CN, alkyl, alkynyl, alkoxy or the phenyl of carbocylic radical substitution.

30. compound or its pharmaceutically acceptable salt as any one of claim 24-27, wherein R⁵It is heteroaryl.

31. compound as claimed in claim 30 or its pharmaceutically acceptable salt, wherein the heteroaryl be optionally by Halogen ,-CN, alkyl, alkynyl, alkoxy or the pyridine radicals of carbocylic radical substitution.

32. a kind of pharmaceutical composition, comprising the compound of any one of preceding claims or its pharmaceutically acceptable salt and At least one pharmaceutically acceptable excipient.

33. a kind of method for inhibition of histone demethylase, methods described includes making the histone demethylase with before State the compound contact of any one of claim.

34. a kind of method for being used to treat the cancer in its subject is needed, methods described includes applying to the subject With the composition for including the compound of any one of preceding claims or its pharmaceutically acceptable salt.